Dialysis system

ABSTRACT

A dialysis system includes a filtration system capable of filtering a water stream, a water purification system capable of purifying said water stream in a non-batch process, a mixing system capable of producing a stream of dialysate from mixing one or more dialysate components with the water stream in a non-batch process, and a dialyzer system. The dialyzer may be a microfluidic dialyzer capable of being fluidly coupled to the stream of dialysate and a blood stream.

RELATED APPLICATIONS

This application is related to the following U.S. Patent Applications:(1) U.S. patent application entitled “Microfluidic Devices,” filed onJun. 7, 2010, and naming M. Kevin Drost, Goran Jovanovic, Todd Miller,James R. Curtis, Bruce Johnson, Alana Warner-Tuhy, Eric Anderson andJulie Wrazel, which claims priority to U.S. Provisional PatentApplication Ser. No. 61/220,117, filed on Jun. 24, 2009; (2) U.S. patentapplication entitled “Dialysis System With Ultrafiltration Control,”filed on Jun. 7, 2010, and naming James R. Curtis, Ladislaus F. Norm andJulie Wrazel, which claims priority to U.S. Provisional PatentApplication Ser. No. 61/267,043, filed on Dec. 5, 2009; and (3) U.S.patent application entitled “Fluid Purification System,” filed on Jun.7, 2010, and naming Richard B. Peterson, James R. Curtis, Hailei Wang,Robbie Ingram-Gobel, Luke W. Fisher and Anna E. Garrison. Thedisclosures of the aforementioned patent applications are incorporatedherein by reference in their entirety.

FIELD

The present disclosure concerns a dialysis system, such as amicrofluidic or flow field dialyzer capable of being fluidly coupled toa dialysate stream and a blood stream, and a method for using thedialysis system.

BACKGROUND

There are, at present, hundreds of thousands of patients in the UnitedStates with end-stage renal disease. Most of those require dialysis tosurvive. United States Renal Data System projects the number of patientsin the U.S. on dialysis will climb past 600,000 by 2012. Many patientsreceive dialysis treatment at a dialysis center, which can place ademanding, restrictive and tiring schedule on a patient. Patients whoreceive in-center dialysis typically must travel to the center at leastthree times a week and sit in a chair for 3 to 4 hours each time whiletoxins and excess fluids are filtered from their blood. After thetreatment, the patient must wait for the needle site to stop bleedingand blood pressure to return to normal, which requires even more timetaken away from other, more fulfilling activities in their daily lives.Moreover, in-center patients must follow an uncompromising schedule as atypical center treats three to five shifts of patients in the course ofa day. As a result, many people who dialyze three times a week complainof feeling exhausted for at least a few hours after a session.

Given the demanding nature of in-center dialysis, many patients haveturned to home dialysis as an option. Home dialysis provides the patientwith scheduling flexibility as it permits the patient to choosetreatment times to fit other activities, such as going to work or caringfor a family member. Unfortunately, current dialysis systems aregenerally unsuitable for use in a patient's home. One reason for this isthat current systems are too large and bulky to fit within a typicalhome. Current dialysis systems are also energy-inefficient in that theyuse large amounts of energy and require enormous amounts of water forproper use. Although some home dialysis systems are available, theygenerally use complex flow-balancing technology that is relativelyexpensive to manufacture and most systems are designed with a system ofsolenoid valves that create high noise levels. As a result, mostdialysis treatments are performed at dialysis centers.

SUMMARY

In view of the foregoing, there is a need for improved dialysis systemsthat are suited for use in a home, either for daily use or nocturnaluse. Disclosed is a dialysis system that is smaller, more portable,consumes less water, utilizes much lower flow rates of dialysate andblood than are presently used in current dialysis systems, and enablesbetter control over levels of ultrafiltration and diafiltration than docurrent systems. The system is compact and light-weight relative toexisting systems and consumes relatively low amounts of energy. Thesystem can be connected to a residential source of water (such as arunning water tap to provide a continuous or semi-continuous householdstream of water) and can produce real-time pasteurized water for use inhome dialysis, without the need to heat and cool large, batchedquantities of water.

In one aspect, there is disclosed a medical system, comprising: afiltration system capable of filtering a water stream; a waterpurification system capable of purifying said water stream in anon-batch process; a mixing system capable of producing a stream ofdialysate from mixing one or more dialysate components with the waterstream in a non-batch process; and a dialyzer system, comprising: amicrofluidic dialyzer capable of being fluidly coupled to the stream ofdialysate and a blood stream, the dialyzer having a membrane separatingthe stream of dialysate from the blood stream, the membrane facilitatingdialysis of the blood stream; a plurality of pumps capable of pumpingthe stream of dialysate across the dialyzer; and a controlleroperatively coupled to the plurality of pumps, the controller capable ofcontrolling a flow rate of the dialysate stream through one or more ofthe plurality of pumps so as to perform one or both of the processes ofultrafiltration and hemodiafiltration on the blood stream while theblood stream is undergoing dialysis.

In another aspect, there is disclosed a dialysis system, comprising: awater purification system adapted to process a water source, such as ahousehold water stream, in a non-batch process to produce anultra-high-temperature-pasteurized water stream; a dialysate preparationsystem adapted to mix the ultra-high-temperature-pasteurized waterstream with dialysate components to produce dialysate; and a dialyzerhaving a blood flow pathway through which blood flows and a dialysateflow pathway through which the dialysate flows, the dialyzer adapted toperform dialysis on the blood.

Other features and advantages should be apparent from the followingdescription of various embodiments, which illustrate, by way of example,the principles of the disclosed devices and methods.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a high level, schematic view of a dialysis system.

FIG. 2 shows a high level, schematic view of a water purification systemof the dialysis system.

FIG. 3 shows a schematic, plan view of an exemplary embodiment of amicrofluidic heat exchange system adapted to heat and cool a singlefluid without the use of a second fluid stream to add heat to or removeheat from the fluid.

FIG. 4A shows an exemplary embodiment of an inlet lamina that forms atleast one inlet pathway where fluid flows in an inward direction throughthe heat exchange system.

FIG. 4B shows an exemplary embodiment of an outlet lamina that forms atleast one outlet pathway where fluid flows in an outward directionthrough the heat exchange system.

FIG. 4C shows the inlet lamina and outlet lamina superimposed over oneanother showing both an inlet pathway and an outlet pathway.

FIG. 5 shows an enlarged view of an inlet region of the inlet lamina.

FIG. 6 shows an enlarged view of a heater region of the inlet lamina.

FIG. 7 shows an enlarged view of a residence chamber of both the inletlamina and outlet lamina.

FIG. 8A shows a plan view of another embodiment of an inlet lamina.

FIG. 8B shows a plan view another embodiment of an outlet lamina.

FIG. 9 shows a perspective view of an exemplary stack of laminae.

FIG. 10 shows a perspective view of an example of an assembledmicrofluidic heat exchange system.

FIG. 11 shows a schematic view of an exemplary heater control systemcoupled to the microfluidic heat exchange system.

FIG. 12 shows a schematic, plan view of another exemplary embodiment offlow pathways for the microfluidic heat exchange system.

FIG. 13A shows another embodiment of an inlet lamina that forms an inletpathway where fluid flows in an inward direction through the heatexchange system.

FIG. 13B shows another embodiment of an outlet lamina that forms anoutlet pathway where fluid flows in an outward direction through theheat exchange system.

FIG. 14 shows a schematic view of an exemplary heater control system.

FIG. 15 shows a high level, schematic view of a dialysate preparationsystem of the dialysis system.

FIG. 16 is a schematic, cross-sectional view of a dialyzer of thedialysis system.

FIG. 17 shows a schematic view of a flow balance system.

FIG. 18 shows a schematic view of another embodiment of a flow balancesystem.

FIG. 19 shows a schematic representation of the flow balance systemrunning in a calibration mode.

FIG. 20 shows a schematic representation of the flow balances systemrunning in a dialysis mode.

FIG. 21 is a schematic view of a microfluidic transfer device having athrough-flow via.

FIG. 22 is a perspective view of one embodiment of a single layer of themicrofluidic transfer device.

FIG. 23 is a plan view of microfluidic flow field with wall segmentsupports.

FIG. 24 is a plan view of a microfluidic flow field with angled wallsegments.

FIG. 25 is a schematic plan view of the juxtaposition of flow fieldswith angled wall segments.

FIG. 26A is a plan view of a microfluidic flow field with cylindricalsupports.

FIG. 26B shows a top view of a pair of cylindrical supports.

FIG. 26C shows a side view of a pair of cylindrical supports.

FIG. 27 is a plan close-up view of a microfluidic flow field withtear-drop shaped support structures.

FIG. 28 is a plan close-up view of a microfluidic flow field havinggradient support structure density and size.

FIG. 29 is a plan close-up view of a microfluidic, flow field withrandomly distributed support structures.

FIG. 30 is a partial perspective view of an assembled device showingfluid inlets and outlets.

FIG. 31 is a perspective view of two combined assembled devices withfluidic headers attached.

FIG. 32 is an assembly view of one embodiment of a microfluidic transferdevice with single-sided lamina.

FIG. 33 is a plan view of one embodiment of a lamina.

FIG. 34 is a perspective view of the assembled device shown in FIG. 26.

FIG. 35 is a detail view of the internal fluid flow paths in the deviceof FIG. 26.

FIG. 36 is a schematic plan view of the juxtaposition of fluid headersand microchannels of adjacent layers, having cross-current flow.

FIG. 37 is a partial schematic plan view of the juxtaposition ofadjacent layers having the flow field shown in FIG. 23.

FIG. 38 is a detail view of the internal fluid flow paths of oneembodiment having single-sided mirrored design.

FIG. 39 is a detail perspective view of the fluid flow paths of a oneembodiment having a single-sided mirrored design with parallelmicrochannels.

FIG. 40 is a partial assembly view of one embodiment of a microfluidictransfer device having double-sided laminae.

FIG. 41 is a plan view of a double-sided lamina.

FIG. 42 is a plan view of a transfer layer.

FIG. 43 is a detail view of the flow path of a microfluidic transferdevice having double sided laminae.

FIG. 44 is a detail view of the flow path of a microfluidic transferdevice having double sided laminae with concurrent flow.

FIG. 45 is a plan view of a lamina having through-cut microchannels.

FIG. 46 is a detail plan view of a lamina having through-cutmicrochannels with lateral supports.

FIG. 47 is a detail plan view of a lamina having through-cutmicrochannels with a herringbone pattern.

FIG. 48 is a detail perspective view of a lamina having through-cutmicrochannels with a herringbone pattern.

FIG. 49 is an assembly view of a microfluidic transfer device havingthrough-cut laminae.

FIG. 50 is a detail view of the fluid flow path of a device havingthrough-cut laminae.

FIG. 51 is a perspective view of a device having alternating paralleland orthogonal through-cut microchannels.

FIG. 52 is a plan view of the juxtaposition of the layers of a subunitincorporating a fluid membrane.

FIG. 53 is a schematic view of a device having fluid membranes.

FIG. 54 is a schematic view of a device having fuel cells.

FIG. 55 is a plan view of an embodiment of a lamina of a flow fielddialyzer without header regions.

FIG. 56 is a plan view of another embodiment of a lamina of a flow fielddialyzer without header regions.

FIG. 57 is a plan, schematic view of a pathway of lasers for forming aflow field.

FIG. 58 is an enlarged view of a portion of a lamina where laser-formedchannels intersect.

FIG. 59 is an enlarged view of a lamina surface showing undulatingchannels and pins formed between the channels.

FIG. 60 is an embodiment where alternating headerless laminae arestacked in a cross-current manner.

DETAILED DESCRIPTION

In order to promote an understanding of the principals of thedisclosure, reference is made to the drawings and the embodimentsillustrated therein. Nevertheless, it will be understood that thedrawings are illustrative and no limitation of the scope of thedisclosure is thereby intended. Any such alterations and furthermodifications in the illustrated embodiments, and any such furtherapplications of the principles of the disclosure as illustrated hereinare contemplated as would normally occur to one of ordinary skill in theart.

FIG. 1 shows a high level, schematic view of a dialysis system. Thedialysis system includes a plurality of subsystems that collectivelyoperate to receive and purify water, use the water to prepare dialysate,and supply the dialysate to a dialyzer that performs various types ofdialysis on the blood of a patient such as hemodialysis, ultrafiltrationand hemodiafiltration. The dialysis system includes plumbing thatprovides fluid pathways for water, dialysis, and blood to flow throughthe dialysis system, as well as one or more pumps that interface withthe plumbing for driving fluid flow through the system. The dialysissystem can also include one or more sensors, such as fluid flow sensors,pressure sensors, conductivity sensors, etc. for sensing and reportingone or more characteristics of fluid flowing through the system.

In an embodiment, the entire dialysis system (including the waterpreparation and purification system, dialysate preparation system, flowbalancer system, dialyzer, and hardware, such as plumbing and sensors)is contained within a single housing that is compact and portable. Inaddition, the dialysis system can prepare dialysate using a tap water,such as in a home or hotel room. In an embodiment, the entire dialysissystem consumes less than about 22″ by 14″ by 9″ of space when dry,which generally corresponds to the size limit for carry-on baggage of anairline. In an embodiment, the entire dialysis system weighs less thanabout fifty pounds when dry.

With reference still to FIG. 1, the dialysis system includes a waterpreparation and purification system 5 that purifies water from a watersupply 7. The water purification system 5 supplies the purified water toa dialysate preparation system 10 that uses the purified water toprepare dialysate. The dialysis system further includes a dialyzer 15that receives the dialysate from the dialysate preparation system 10 andperforms dialysis on a patient's blood. In an embodiment, the dialyzer15 and the dialysate preparation system 10 both interface with a flowbalancer system 20 that regulates the flow of dialysate to the dialyzerto achieve different types of dialysis, including hemodialysis,ultrafiltration, and hemodiafiltration, as described in detail below.

Diffusion is the principal mechanism in which hemodialysis removes wasteproducts such as urea, creatinine, phosphate and uric acid, amongothers, from the blood. A differential between the chemical compositionof the dialysate and the chemical composition of the blood within thedialyzer causes the waste products to diffuse through a membrane fromthe blood into the dialysate. Ultrafiltration is a process in dialysiswhere fluid is caused to move across the membrane from the blood intothe dialysate, typically for the purpose of removing excess fluid fromthe patient's blood stream. Along with water, some solutes are alsodrawn across the membrane via convection rather than diffusion.Ultrafiltration is a result of a pressure differential between a bloodcompartment and a dialysate compartment in the dialyzer where fluidmoves from a higher pressure to a lower pressure. In some circumstances,by design or unintentional consequence, fluid in the dialysatecompartment is higher than the blood compartment causing fluid to movefrom the dialysate compartment into the blood compartment. This iscommonly referred to as reverse ultrafiltration.

In hemodiafiltration, a high level of ultrafiltration is created,greater than the amount required to remove fluid from the patient'sblood, for the purpose of increasing convective solute transport acrossthe membrane. The amount of fluid in excess of what is required to beremoved from the patient's blood must therefore be returned to the bloodstream in order to avoid an adverse hemodynamic reaction. This isaccomplished by intentionally increasing the pressure in the dialysatecompartment of the dialyzer to cause the appropriate amount of reverseultrafiltration. This process of ultrafiltration alternating withreverse ultrafiltration is often referred to as “push-pullhemodiafiltration.” This is a significant improvement over more commonmethods of hemodiafiltration where sterile fluid is administered to thepatient in a location outside of the dialyzer.

In use, the patient is coupled to the dialyzer 15 such that thepatient's blood flows into and out of the dialyzer 15 using devices andtechniques known to those skilled in the art. The dialysis systemprepares dialysate using water from a household water source, such as atap, that has been previously prepared through filtration andpurification before being mixed with various dialysate components tomake the dialysate, and then flows the dialysate through the dialyzer incommunication with the blood such that one or more of the dialysisprocesses on the blood is performed. The water purification systemincludes a plurality of subsystems that collectively operate to purifythe water including pasteurization of the water, as described more fullybelow. The purified water is then mixed with dialysate concentrates toform dialysate, which is supplied to the dialyzer 15 and to the flowbalancer system, which regulates the flow of dialysate to the dialyzer15 to selectively achieve different types of dialysis, includinghemodialysis, ultrafiltration, and hemodiafiltration, as described morefully below. The dialysis system supplies the used dialysate to a drain25. In an embodiment, the system recaptures heat from the used dialysatebefore going to the drain.

I. Exemplary Subsystems of Dialysis System

Exemplary embodiments of the various subsystems of the dialysis systemare now described, including the water purification system 5, dialysatepreparation system 10, dialyzer 15, and flow balancer system 20. Itshould be appreciated that the descriptions are exemplary and thatvariations are possible.

1. Water Purification System

FIG. 2 shows a high level, schematic view of the water purificationsystem 5. The water purification system 5 includes a plurality ofsubsystems and/or components each of which is schematically representedin FIG. 2. Although it is described in the context of purifying water,the water purification system 5 can be used to purify fluids other thanwater. Water enters the fluid purification system at an entry location105 (from the water supply 7 in FIG. 1) and communicates with each ofthe subsystems and components as the water flows along a flow pathwaytoward the dialysate preparation system 10. The subsystems may include,for example, a sediment filter system 115, a carbon filter system 120, areverse osmosis system 125, an ultrafilter system 130, an auxiliaryheater system 135, a degassifier system 140, or any combination thereof.

Upon exiting the fluid purification system 5, and prior to entering thedialysate preparation system 10, the fluid is in a purified state. Thispreferably includes the fluid being in a pasteurized state although thefluid system does not necessarily pasteurize the fluid in allcircumstances. The embodiment shown in FIG. 2 is exemplary and not allof the components shown in FIG. 2 are necessarily included in the waterpurification system 5. The individual components included in the systemmay vary depending on the type and level of purification orpasteurization required. The quantity and sequential order of thesubsystems along the flow pathway shown in FIG. 2 is for purposes ofexample and it should be appreciated that variations are possible.

An exemplary method for purifying water using the fluid purificationsystem 5 is now described including a description of a fluid flow paththrough the system. As mentioned, water enters the water purificationsystem 5 via an entry location 105. The entry location may include athree-way valve that may be set such that incoming water is receivedfrom one of at least two water sources. One such water source may behousehold water tap. Alternately, the valve may be set to receiverecirculated water that was previously routed through the waterpurification system 5 and that is re-routed back into the system such asto flush the system. When the valve is set to receive recirculatedwater, the re-circulated water may bypass one or more of the subsystemsas it flows through the water purification system 5.

When the valve is set to receive water from the household water tap, theincoming water first flows through at least one sediment filter system115, which includes one or more sediment filters that filter sedimentfrom the water flowing therethrough. In an embodiment, the sedimentfilter 115 removes particulate matter down to 5 microns or even 1micron. A pressure sensor may be positioned upstream of the sedimentfilter(s) and a pressure sensor may also be positioned downstream of thesediment filter(s) in order to monitor flow conditions. In addition, theflow pathway may include one or more pressure regulators configured toregulate fluid pressure to achieve a desired flow rate through thesystem. The pressure regulator(s) may be used to compensate for ahousehold tap having a flow rate that is above or below a desired range.

The water then flows through a carbon filter system 120, which includesone or more carbon filters that filter materials such as organicchemicals, chlorine and chloramines from the water. In an embodiment,the carbon filter system 120 includes two carbon filters with a sampleport positioned in the flow path between the carbon filters. The sampleport provides an operator with access to the water flowing through thesystem, such as for quality control purposes. In an embodiment, at leastone pressure sensor and at least one conductivity sensor are positionedin the flow pathway downstream of the carbon filter system 120. Theconductivity sensor provides an indication as to the percentage ofdissolved solids removed from the water. In addition, one or more pumpsmay be positioned at various locations along the water flow pathway suchas between the filter subsystems.

The water flows from the carbon filter system 120 to a reverse osmosissystem 125 configured to remove particles from the water pursuant areverse osmosis procedure. The reverse osmosis system 125 usuallyremoves greater than 95% of the total dissolved solids from the water.The reverse osmosis system 125 may have two outlets including a wastewater outlet 126 and a pure water outlet 127. The waste water outlet 126outputs waste water from the reverse osmosis system 125. The waste watercan be rerouted back into an upstream location of the water pathway forre-entry into the reverse osmosis system 125. In this regard, a sensorsuch as a conductivity sensor may be located upstream of the reverseosmosis system 125 as a means of verifying the contents of the water.Alternately, the waste water outlet 126 may supply the waste water to adrain.

The sediment filter system 115, carbon filter system 120, and reverseosmosis system 125 collectively form a pre-processing stage that removesa majority of dissolved solids, bacteria contamination, and chemicalcontamination, if any, from the water. The water is therefore in asomewhat macro-purified state as it exits the pre-processing stage.Thus, the preprocessing stage supplies relatively clean water to thedownstream pump(s) and also to a downstream heat exchange system 110that pasteurizes the water. The preprocessing stage reduces oreliminates the potential for scale build-up and corrosion during heatingof the water by the heat exchange system 110.

One or more degassifier systems 140 may be positioned in the flowpathway upstream and/or downstream of the heat exchange system 110 forremoving entrained gas from the water. The degassifier system 140 mayinclude any of a variety of components adapted to remove entrained gasfrom the water. For example, the degassifier systems 140 may include aspray chamber and/or a bubble trap.

After the water passes the pre-processing stage, the water flows througha pump 150 that pumps the water into the heat exchange (HEX) system 110.The heat exchange system 110 heats the water to a temperature thatachieves pasteurization of the water. In an embodiment, the heatexchange system 110 is a microfluidic heat exchange system. Severalexemplary embodiments of microfluidic heat exchange systems aredescribed in detail below. The heat exchange system 110 may be encasedin insulation to reduce the likelihood of heat loss of the water passingtherethrough.

The pump 150 may be used to increase the water pressure to a levelhigher than the saturation pressure encountered in the heat exchangesystem 110. This prevents phase change of the water inside the heatexchange system 110. Thus, if the highest temperature reached in theheat exchange system 110 is 150 degrees Celsius where the water wouldhave a saturation pressure known to one of skill in the art, thepressure of the water coming out of the pump would exceed thatsaturation pressure by a certain safety margin, such as 10 psi, toensure that no phase change occurs. The pump desirably increases thewater pressure to a level that is at or exceeds the saturation pressureto ensure no localized boiling. This can be important where the heatexchange system is used to pasteurize water and the water is exposed tohigh temperatures that may be greater than 138 degrees Celsius, i.e.,well above the boiling point of water at atmospheric pressure.

After leaving the heat exchange system 110, the water passes into athrottling valve 160, such as flow restrictor, which maintains thepressure though the water path from the pump 150 to outlet of the heatexchange system 110. The throttling valve 160 and the pump 150 may becontrolled and adjusted to achieve a flow rate and a desired pressureconfiguration. The pump 150 and the throttling valve 160 may communicatewith one another in a closed loop system to ensure the required pressureis maintained for the desired flow rate and temperature. One or moretemperature sensors and/or flow sensors may be positioned along the flowpathway downstream of the heat exchange system for use in controllingthe pump 150 and the throttling valve 160.

After the water leaves the throttling valve 160, it passes to anultrafilter (UF) system 130 that removes macromolecules and all orsubstantially all of the dead bacteria killed by the pasteurizationprocess from the water to ensure no endotoxins remain in the waterbefore mixing the dialysate. The presence of macromolecules may bedetrimental to the dialysis process. The water then passes through aheater system 135 that may, if necessary or desired, heat the water to adesired temperature, such as to normal body temperature (98.6 degreesFahrenheit). From the heater system 135, the water passes to thedialysate preparation system 10.

In an embodiment, a second heat exchange system is positioned in theflow pathway upstream of the heater system 135. The second heat exchangesystem is used to further cool the water that comes out of the heatexchange system 110 in the event that the water is above a predetermineddesired temperature, such as 37 degrees Celsius. The second heatexchange system may be connected to a separate source of cool water thatwill then act as a cooling agent or it can be connected to the waterrejected from the reverse osmosis system 125. The second heat exchangesystem may be used in environments where the water source produces verywarm water and/or when the heat exchange system 110 is unable to coolthe water sufficiently for use in dialysis.

2. Microfluidic Heat Exchange System

As discussed above, the water purification system 5 may employ a heatexchange system 110 that is adapted to pasteurize the water. FIG. 3shows a schematic, plan view of an exemplary embodiment of themicrofluidic heat exchange system 110, which is configured to achievepasteurization of a liquid (such as water) flowing through themicrofluidic heat exchange system without the need for a second fluidstream to add heat to or remove heat from the liquid. FIG. 3 isschematic and it should be appreciated that variations in the actualconfiguration of the flow pathway, such as size and shape of the flowpathway, are possible.

As described more fully below, the microfluidic heat exchange systemdefines a fluid flow pathway that includes (1) at least one fluid inlet;(2) a heater region where incoming fluid is heated to a pasteurizationtemperature via at least one heater; (3) a residence chamber where fluidremains at or above the pasteurization temperature for a predeterminedtime period; (4) a heat exchange section where incoming fluid receivesheat from hotter (relative to the incoming fluid) outgoing fluid, andthe outgoing fluid cools as it transfers heat to the incoming fluid; and(5) a fluid outlet where outgoing fluid exits in a cooled, pasteurizedstate. Depending on the desired temperature of the outgoing fluid, oneor more additional heat exchanges may be used downstream to adjust theactual temperature of the outgoing fluid to the desired temperature foruse, for example, in dialysis. This is especially true in warmerclimates, where incoming water may be tens of degrees higher than watersupplied in colder climates, which will result in higher outlettemperatures than may be desired unless further cooling is applied.

In an embodiment, the flow pathway is at least partially formed of oneor more microchannels, although utilizing microfluidic flow fields asdisclosed below for portions of the fluid flow pathway such as the heatexchange section is also within the scope of the invention. Therelatively reduced dimensions of a microchannel enhance heat transferrates of the heat exchange system by providing a reduced diffusionalpath length and amount of material between counterflow pathways in thesystem. In an embodiment, a microchannel has at least one dimension lessthan about 1000 μm. The dimensions of a microchannel can vary and aregenerally engineered to achieve desired heat transfer characteristics. Amicrochannel in the range of about 0.1 to about 1 mm in hydraulicdiameter generally achieves laminar fluid flow through the microchannel,particularly in a heat exchange region of the microchannel. The smallsize of a microchannel also permits the heat exchange system 110 to becompact and lightweight. In an embodiment, the microchannels are formedin one or more laminae that are arranged in a stacked configuration, asformed below.

The flow pathway of the microfluidic heat exchange system 110 may bearranged in a counterflow pathway configuration. That is, the flowpathway is arranged such that cooler, incoming fluid flows in thermalcommunication with hotter, outgoing fluid. The hotter, outgoing fluidtransfers thermal energy to the colder, incoming fluid to assist theheaters in heating the incoming fluid to the pasteurization temperature.This internal preheating of the incoming fluid to a temperature higherthan its temperature at the inlet reduces the amount of energy used bythe heaters to reach the desired peak temperature. In addition, thetransfer of thermal energy from the outgoing fluid to the incoming fluidcauses the previously heated, outgoing fluid to cool prior to exitingthrough the fluid outlet. Thus, the fluid is “cold” as it enters themicrofluidic heat exchange system 110, is then heated (first via heatexchange and then via the heaters) as it passes through the internalfluid pathway, and is “cold” once again as it exits the microfluidicheat exchange system 110. In other words, the fluid enters themicrofluidic heat exchange system 110 at a first temperature and isheated (via heat exchange and via the heaters) to a second temperaturethat is greater than the first temperature. As the fluid follows an exitpathway, the fluid (at the second temperature) transfers heat toincoming fluid such that the fluid drops to a third temperature that islower than the second temperature and that is higher than the firsttemperature.

Exemplary embodiments of a fluid pathway and corresponding components ofthe microfluidic heat exchange system 110 are now described in moredetail with reference to FIG. 3, which depicts a bayonet-style heatexchanger, with the inlet and outlet on one side of the device, acentral heat exchange portion, and a heating section toward the oppositeend. The fluid enters the microfluidic heat exchange system 110 throughan inlet 282. In the illustrated embodiment, the flow pathway branchesinto one or more inflow microchannels 284 that are positioned in acounterflow arrangement with an outflow microchannel 286. As mentioned,microfluidic heat exchange system 110 may be formed by a stack oflayered lamina. The inflow microchannels 284 may be positioned inseparate layers with respect to the outflow microchannels 286 such thatinflow microchannels 284 are positioned above or below the outflowmicrochannels 286 in an interleaved fashion. In another embodiment, theinflow microchannels 284 and outflow microchannels 286 are positioned ona single layer.

The outflow microchannel 286 communicates with an outlet 288. In theillustrated embodiment, the inlet 282 and outlet 288 are positioned onthe same end of the microfluidic heat exchange system 110, although theinlet 282 and outlet 288 may also be positioned at different positionsrelative to one another.

The counterflow arrangement places the inflow microchannels 284 inthermal communication with the outflow microchannel 286. In this regard,fluid in the inflow microchannels 284 may flow along a directionalvector that is oriented about 180 degrees to a directional vector offluid flow in the outflow microchannels 286. The inflow and outflowmicrochannels may also be in a cross flow configuration wherein fluid inthe inflow microchannels 284 may flow along a directional vector that isoriented between about 180 degrees to about 90 degrees relative to adirectional vector of fluid flow in the outflow microchannels 286. Theorientation of the inflow microchannels relative to the outflowmicrochannels may vary in any matter that is configured to achieve thedesired degree of thermal communication between the inflow and outflowmicrochannels.

One or more heaters 292 are positioned in thermal communication with atleast the inflow microchannels 284 such that the heaters 292 can provideheat to fluid flowing in the system. The heaters 292 may be positionedinside the inflow microchannels 284 such that fluid must flow aroundmultiple sides of the heaters 292. Or, the heaters 292 may be positionedto the side of the inflow microchannels 284 such that fluid flows alongone side of the heaters 292. In any event, the heaters 292 transfer heatto the fluid sufficient to cause the temperature of the fluid to achievea desired temperature, which may include a pasteurization temperature inthe case of water to be purified. In an embodiment, the fluid is waterand the heaters 292 assist in heating the fluid to a temperature of atleast 100 degrees Celsius at standard atmospheric pressure. In anembodiment, the fluid is water and the heaters 292 assist in heating thefluid to a temperature of at least 120 degrees Celsius. In anembodiment, the fluid is water and the heaters 292 assist in heating thefluid to a temperature of at least 130 degrees Celsius. In anembodiment, the fluid is water and the heaters 292 assist in heating thefluid to a temperature of at least 138 degrees Celsius. In anotherembodiment, the fluid is water and is heated to a temperature in therange of about 138 degrees Celsius to about 150 degrees Celsius. Inanother embodiment, the fluid is heated to the highest temperaturepossible without achieving vaporization of the fluid.

Thus, the microfluidic heat exchange system 110 may maintain the fluidas a single phase liquid. Because water typically changes phases from aliquid into a gaseous state around 100 degrees Celsius, heating water tothe temperatures set forth above requires pressurization of the heatexchange system so that the single-phase liquid is maintainedthroughout. Pressures above the saturation pressure corresponding to thehighest temperature in the heat exchange system are sufficient tomaintain the fluid in a liquid state. As a margin of safety, thepressure is typically kept at 10 psi or higher above the saturationpressure. In an embodiment, the pressure of water in the microfluidicheat exchange system is maintained greater than 485 kPa to preventboiling of the water, and may be maintained significantly in excess ofthat level, such as 620 kPa or even as high as 900 kPa, in order toensure no boiling occurs. These pressures are maintained in the heatexchange system using a pump and a throttling valve. A pump upstream ofthe heat exchange system and a throttling valve downstream of the heatexchange system are used where the pump and throttling valve operate ina closed loop control setup (such as with sensors) to maintain thedesired pressure and flow rate throughout the heat exchange system.

Once the fluid has been heated to the pasteurization temperature, thefluid passes into a residence chamber 294 where the fluid remains heatedat or above the pasteurization temperature for a predetermined amount oftime, referred to as the “residence time”, or sometimes referred to asthe “dwell time”. In an embodiment, the dwell time can be less than orequal to one second, between one and two seconds, or at least about twoseconds depending on the flow path length and flow rate of the fluid.Higher temperatures are more effective at killing bacteria and shorterresidence times mean a more compact device. Ultrahigh temperaturepasteurization, that is designed to kill all Colony Forming Units (CFUs)of bacteria down to a concentration of less than 10⁻⁶ CFU/ml (such asfor purifying the water for use with infusible dialysate), is defined tobe achieved when water is heated to a temperature of 138 degrees Celsiusto 150 degrees Celsius for a dwell time of at least about two seconds.Ultrapure dialysate has a bacterial load no greater than 0.1 CFU/ml.Table 1 (shown in the attached figures) indicates the requiredtemperature and residence time to achieve various levels ofpasteurization. The heat exchange system described herein is configuredto achieve the various levels of pasteurization shown in Table 1.

The fluid then flows from the residence chamber 294 to the outflowmicrochannel 286, where it flows toward the fluid outlet 288. Asmentioned, the outflow microchannel 286 is positioned in a counterflowrelationship with the inflow microchannel 284 and in thermalcommunication with the inflow microchannel 284. In this manner, outgoingfluid (flowing through the outflow microchannel 286) thermallycommunicates with the incoming fluid (flowing through the inflowmicrochannel 284). As the heated fluid flows through the outflowmicrochannel 286, thermal energy from the heated fluid transfers to thecooler fluid flowing through the adjacent inflow microchannel 284. Theexchange of thermal energy results in cooling of the fluid from itsresidence chamber temperature as it flows through the outflowmicrochannel 286. Moreover, the incoming fluid is preheated via the heatexchange as it flows through the inflow microchannel 284 prior toreaching the heaters 292. In an embodiment, the fluid in the outflowmicrochannel 284 is cooled to a temperature that is no lower than thelowest possible temperature that precludes bacterial infestation of thefluid. When the heat exchange system pasteurizes the fluid, bacteria inthe fluid down to the desired level of purification are dead as thefluid exits the heat exchange system. In such a case, the temperature ofthe fluid after exiting the heat exchange system may be maintained atroom temperature before use in dialysis. In another embodiment, thefluid exiting the heat exchange system is cooled to a temperature at orbelow normal body temperature.

Although an embodiment is shown in FIG. 3 as having an outlet channelsandwiched between an inflow channel, other arrangements of the channelsare possible to achieve the desired degrees of heating and cooling andenergy requirements of the heaters. Common to all embodiments, however,is that all fluid pathways within the system are designed to be traveledby a single fluid, without the need for a second fluid to add heat to orremove heat from the single fluid. In other words, the single fluidrelies on itself, at various positions in the fluid pathway, to heat andcool itself.

The dimensions of the microfluidic heat exchange system 110 may vary. Inan embodiment, the microfluidic heat exchange system 110 is sufficientlysmall to be held in the hand of a user. In another embodiment, themicrofluidic heat exchange system 110 is a single body that weighs lessthan 5 pounds when dry. In another embodiment, the microfluidic heatexchange portion 350 of the overall system 110 has a volume of about onecubic inch. The dimensions of the microfluidic heat exchange system 110may be selected to achieve desired temperature and dwell timecharacteristics.

As mentioned, an embodiment of the microfluidic heat exchange system 110is made up of multiple laminar units stacked atop one another to formlayers of laminae. A desired microfluidic fluid flow path may be etchedinto the surface of each lamina such that, when the laminae are stackedatop one another, microfluidic channels or flow fields are formedbetween the lamina. Furthermore, both blind etching and through etchingmay be used for forming the channels in the laminae. In particular,through etching allows the fluid to change the plane of laminae and moveto other layers of the stack of laminae. This occurs in one embodimentat the outlet of the inflow laminae where the fluid enters the heatersection, as described below. Through etching allows all laminae aroundthe heater section to participate in heating of the fluid instead ofmaintaining the fluid only in the plane of the inlet laminae. Thisembodiment provides more surface area and lower overall fluid velocityto facilitate the heating of the fluid to the required temperature andultimately contributes to the efficiency of the device.

The microchannels or flow fields derived from blind and/or throughetching of the laminae form the fluid flow pathways. FIG. 4A shows aplan view of an exemplary embodiment of an inlet lamina 305 that formsat least one inlet pathway where fluid flows in an inward direction (asrepresented by arrows 307) through the heat exchange system 110. FIG. 4Bshows a plan view an exemplary embodiment of an outlet lamina 310 thatforms at least one outlet pathway where fluid flows in an outwarddirection (as represented by arrows 312) through the heat exchangesystem 110. The inlet pathway and the outlet pathway may each compriseone or more microchannels. In an embodiment, the inlet and outletpathway comprise a plurality of microchannels arranged in parallelrelationship.

FIGS. 4A and 4B show the lamina 305 and 310 positioned adjacent eachother, although in assembled device the lamina are stacked atop oneanother in an interleaved superimposed over one another showing both theinlet pathway and outlet pathway. The inlet lamina 305 and outlet lamina310 are stacked atop one another with a fluid conduit therebetween sofluid may flow through the conduit from the inlet pathway to the outletpathway, as described more fully below. When stacked, a transfer layermay be interposed between the inlet lamina 305 and the outlet lamina310. The transfer layer is configured to permit heat to transfer fromfluid in the outlet pathway to fluid in the inlet pathway. The transferlayer may be any material capable of conducting heat from one fluid toanother fluid at a sufficient rate for the desired application. Relevantfactors include, without limitation, the thermal conductivity of theheat transfer layer 110, the thickness of the heat transfer layer, andthe desired rate of heat transfer. Suitable materials include, withoutlimitation, metal, metal alloy, ceramic, polymer, or composites thereof.Suitable metals include, without limitation, stainless steel, iron,copper, aluminum, nickel, titanium, gold, silver, or tin, and alloys ofthese metals. Copper may be a particularly desirable material. Inanother embodiment, there is no transfer layer between the inlet andoutlet laminae and the laminae themselves serve as the thermal transferlayer between the flow pathways.

The inlet lamina 305 and outlet lamina 310 both include at least oneinlet opening 320 and at least one outlet opening 325. When the inletlamina 305 and outlet lamina 310 are stacked atop one another andproperly aligned, the inlet openings 320 align to collectively form afluid pathway that extends through the stack and communicates with theinlet pathway of the inlet laminae 305, as shown in FIG. 4C. Likewise,the outlet openings 325 also align to collectively form a fluid pathwaythat communicates with the outlet pathway of the outlet laminae 310. Anyquantity of inlet lamina and outlet lamina can be stacked to formmultiple layers of inlet and outlet pathways for the heat exchangesystem 110. The quantity of layers can be selected to providepredetermined characteristics to the microfluidic heat exchange system110, such as to vary the amount of heat exchange in the fluid, the flowrate of the fluid capable of being handled by the system, etc. In anembodiment, the heat exchange system 110 achieves incoming liquid flowrates of at least 100 ml/min.

In another embodiment, the heat exchange system 110 achieves incomingliquid flow rates of at least 1000 ml/min. Such a heat exchange systemmay be manufactured of a plurality of laminae in which the microfluidicpathways have been formed using a masking/chemical etching process. Thelaminae are then diffusion bonded in a stack, as described in moredetail below. In an embodiment, the stack includes 40-50 laminae with aflow rate of 2-3 ml/min occurring over each lamina. Higher flow ratescan be achieved by increasing the number of pairs of stacked laminaewithin the heat exchanger. In other embodiments, much higher flow ratescan be handled through the system.

In operation, fluid flows into the inlet pathway of the inlet lamina 305via the inlet opening 320. This is described in more detail withreference to FIG. 5, which shows an enlarged view of an inlet region ofthe inlet lamina 305. The inlet opening 320 communicates with an inletconduit 405 that guides the fluid to the inlet pathway. The inletopening 320 may configured with a predetermined size relative to thesize of the inlet conduit 405, which may have a diameter of 2-mm. Forexample, in an embodiment, the inlet opening 320 has an associatedhydraulic diameter that may be about ten to fifteen times larger thanthe hydraulic diameter of the inlet conduit 405. Such a ratio ofhydraulic diameters has been found to force fluid to distributerelatively evenly among the multiple inlet laminae. In anotherembodiment, for a 2-mm wide inlet flow path, a hydraulic diameter ratioof greater than 10:1, such as 15:1, may be used to ensure an evendistribution of fluid flow over the stack.

With reference still to FIG. 5, a downstream end of the inlet conduit405 opens into the inlet pathway, which flares outward in size relativeto the size of the inlet conduit 405. In this regard, one or more flowseparation guides, such as fins 410, may be positioned at the entrywayto the inlet pathway. The flow separation fins are sized and shaped toencourage an even distribution of fluid as the fluid flows into theinlet pathway from the inlet conduit 405. It should be appreciated thatthe size, shape, and contour of the inlet conduit 405 and inlet pathwaymay vary and that the embodiment shown in FIG. 5 is merely exemplary. Byway of example only, this region of the system could also comprise aflow field of pin-shaped members (as described below) around which thefluid flows.

With reference again to FIG. 4A, the inlet pathway and outlet pathwayeach include a heat exchange region. The heat exchange regions arereferred to collectively using the reference numeral 350 andindividually using reference numeral 350 a (for the inlet pathway) andreference numeral 350 b (for the outlet pathway). The heat exchangeregions 350 are the locations where the colder fluid (relative to thefluid in the outlet pathway) of the inlet pathway receives heattransferred from the hotter fluid (relative to the fluid in the inletpathway) of the outlet pathway. As discussed above, the relativelycolder fluid in the inflow pathway is positioned to flow in thermalcommunication with the relatively hotter fluid in the outflow pathway.In this layered embodiment, the inflow pathway is positioned immediatelyabove (or below) the outflow pathway when the lamina are stacked. Heattransfers across the transfer layer from the fluid in the outflowpathway to the fluid in the inflow pathway as a result of thetemperature differential between the fluid in the inflow pathway and thefluid in the outflow pathway and the thermal conductivity of thematerial separating the two pathways. Again rather than comprising aseries of microchannels, the heat exchange regions may also comprise amicrofluidic flow field as described above.

With reference still to FIG. 4A, the fluid in the inflow pathway flowsinto a heater region 355 from the heat exchange region 350. A pluralityof pins 357 may be positioned in the inlet flow pathway between the heatexchange region 350 and the heater region 355. The pins 357 disrupt thefluid flow and promote mixing, which may improve both fluid flow andheat distribution. FIG. 6 shows an enlarged view of the heater region355. In an embodiment, the inflow pathway bifurcates into at least twoflow pathways in the heater region 355 to accommodate a desired flowrate. Alternatively only one flow path through the heater region may beutilized, or three or more flow paths may be selected. The heater region355 includes one or more heaters 292 that thermally communicate withfluid flowing through this region, but are hermetically isolated fromthe flow path. The heaters 292 add heat to the incoming fluid sufficientto raise temperature of the fluid to the desired temperature, which mayinclude a pasteurization temperature. The incoming fluid was previouslypreheated as it flowed through the heat exchange region 350. Thisadvantageously reduced the energy requirements for the heaters.

The laminae in the stack may include through-etches at entry locations505 to the heater region 355 such that fluid entering the heater regioncan pass through all the laminae in the stack. Through etching allowsall laminae around the heater section to participate in heating of thefluid instead of maintaining the fluid only in the plane of the inletlaminae. This provides more surface area between the fluid and theheaters and also provides lower overall fluid velocity to facilitate theheating of the fluid to the required temperature.

As mentioned, the inflow pathway may bifurcate into multiple flowpathways. Each pathway may include one or more heaters 292 arrangedwithin the pathway so as to maximize or otherwise increase the amount ofsurface area contact between the heaters 292 and fluid flowing throughthe pathways. In this regard, the heaters 292 may be positioned towardsthe middle of the pathway such that the fluid must flow around eitherside of the heaters 292 along a semicircular or otherwise curvilinearpathway around the heaters 292. The heaters 292 can vary inconfiguration. In an embodiment, the heaters 292 are conventionalcartridge heaters with a ⅛-inch diameter which can be run in anembodiment at a combined rate of between about 70,000 and 110,000 W/m²,which results in energy usages of less than 100 W in one embodiment, andless than 200 W in another embodiment, for the entire stack running atabout 100 mL/minute. In an embodiment, the system uses six heaters in aconfiguration of three heaters per flow pathway wherein each heater usesabout 70 W for a 100 ml/min flow rate. In an embodiment the fluid isforced to flow around the heaters in paths 1.6 mm wide.

With reference again to FIG. 4A, the inflow pathway transitions from theheater section 355 to the residence chamber 360. By the time the fluidflows into the residence chamber 360, it has been heated to the desiredtemperature, such as the pasteurization temperature, as a result of theheat transfer in the heat exchange region 350 and/or by being heated inthe heater section 355. In the case of multiple laminae being stacked,the residence chamber 360 may be a single chamber that spans all of thelayers of laminae in the stack such that the fluid from each inletlamina flows into a single volume of fluid in the residence chamber 360.The residence chamber 360 is configured such that fluid flow ‘shortcuts’are eliminated, all of the fluid is forced to travel a flow pathway suchthat no portion of the fluid will reside in the residence chamber forthe less than the desired duration at a specified flow rate, and thefluid is maintained at or above the pasteurization temperature for theduration of the time (i.e., the dwell time) that the fluid is within theresidence chamber 360. In effect, the residence time is a result of thedimensions of the flowpath through the residence area and the flow rate.It will thus be apparent to one of skill in the art how to design aresidence pathway for a desired duration.

FIG. 7 shows an enlarged view of the region of the residence chamber 360for the inlet lamina 305 and outlet lamina 310. For clarity ofillustration, FIG. 7 shows the inlet lamina 305 and outlet lamina 310positioned side-by-side although in use the laminae are stacked atop oneanother such that the residence chambers align to form a residencechamber that spans upward along the stack. In an embodiment, theresidence chamber 360 incorporates a serpentine flow path as shown inthe enlarged view of the residence chamber of FIG. 7. The serpentineflow path provides a longer flow path to increase the likelihood of theliquid spending a sufficient amount of time within the residence chamber360.

After the fluid has reached the end of the serpentine flow path, itpasses (represented by arrow 610 in FIG. 7) to the outlet pathway of theoutlet lamina 310. With reference now to FIG. 4B, the outlet pathwaypasses between the heaters 292, which act as insulators for the fluid tolessen the likelihood of the fluid losing heat at this stage of the flowpathway. The heated fluid of the outlet pathway then flows toward theheat exchange region 350 b. The outlet flow pathway expands prior toreaching the heat exchange region 350 b. A set of expansion fans 367directs the fluid into the expanded heat exchange region 350 b of theoutlet pathway, where the fluid thermally communicates with the coolerfluid in the inflow pathway. As discussed, heat from the fluid in thehotter outflow pathway transfers to the cooler fluid in the inflowpathway. This results in cooling of the outflowing fluid and heating ofthe inflowing fluid. The fluid then flows from the heat exchange region350 b to the outlet opening 325. At this stage, the fluid is in acooled, pasteurized state.

In an embodiment, laminae having a thickness of 350 microns with anetch-depth of 175 microns, with 2.5-mm wide channels having a hydraulicdiameter of 327 microns were utilized. Each pair of laminae was able tohandle a fluid flow rate of approximately 3.3 mL/min of fluid, whichthus required 30 pairs of laminae in order to facilitate a flow of 100mL/min, with only a 15 mm long heat exchanger section. In an embodiment,the fluid flowpaths are designed in smooth, sweeping curves and aresubstantially symmetrically designed along the longitudinal axis of thestack; if the flow paths are not designed symmetrically, they aredesigned to minimize differences in the path line or lengths so as toevenly distribute the flow, the heating of the fluid and the variousdwell times.

The width of the ribs separating channels in the heat exchange portioncan be reduced, which would have the effect of increasing the availableheat transfer area and reducing the length of the heat exchange portionrequired for the desired energy efficiency level of the device. Energyefficiency levels of at least about 85%, and in some embodiment of atleast about 90% can be achieved, meaning that 90% of the thermal energyfrom the outgoing fluid can be transferred to the incoming fluid streamand recaptured without loss.

In this manner, a heat exchange system may be constructed to providepasteurized water continuously at a desired flow rate for real-timemixing of dialysate in a dialysis system, without the need either toheat, purify or store water in batched quantities or to provide bags ofpure water or of premixed dialysate for use by the patient. The waterpurification system processes a water source, such as a household waterstream, in a non-batch process to produce anultra-high-temperature-pasteurized water stream.

FIG. 8A shows a plan view of another embodiment of an inlet lamina 705that forms at least one inlet pathway where fluid flows in an inwarddirection (as represented by arrows 707) through the heat exchangesystem 110. FIG. 8B shows a plan view another embodiment of an outletlamina 710 that forms at least one outlet pathway where fluid flows inan outward direction (as represented by arrows 712) through the heatexchange system 110. The flow pathway in this embodiment generallyfollows a different contour than the flow pathway of the embodiment ofFIGS. 4A and 4B. In actual use, the inlet lamina 705 and outlet lamina710 are stacked atop one another.

The fluid enters the inlet pathway of the inlet lamina 705 at an inlet720. The inlet pathway then splits into multiple pathways at the heatexchange region 750 a, which thermally communicates with a correspondingheat exchange region 750 b of the outlet lamina 710. In anotherembodiment, the inlet pathway does not split into multiple pathways butremains a single pathway. The inlet pathway could also be at leastpartially formed of one or more microfluidic flow fields as describedbelow. After the heat exchange region 750 a, the inlet pathwaytransitions to an arc-shaped heater region 760 that thermallycommunicates with a heater 765, such as a 150-Watt McMaster-Carrcartridge heater (model 3618K451). The heater region serves as both aregion where the heater 765 heats the fluid and as a residence chamberwhere the fluid remains heated at or above the desired temperature for apredetermined amount of time.

From the heater region 760 and residence chamber of the inlet lamina705, the fluid flows to the outlet lamina 710 at an entrance location770. The fluid then flows into the heat exchange region 750 b of theoutlet lamina 710, where the fluid transfers heat to the incoming fluidflowing through the heat exchange region 750 a of the inlet lamina 705.The fluid then exits the outlet lamina at an outlet 775. In embodiment,the lamina 705 and 710 are about 600 μm thick and the microfluidic flowpathways have a depth of about 400 μm to 600 μm. In each of theembodiments disclosed herein, the fluid flow path completely encircleseach of the heaters so that any shim material conducting heat away fromthe heater will have fluid flowing over it to receive the heat, therebyminimizing heat loss to the environment. In addition, ideally, theflowpaths around each heater will be relatively narrow so thatnon-uniform heating due to separation from the heaters will be avoided.

As mentioned, the microfluidic heat exchange system 110 may be formed ofa plurality of lamina stacked atop one another and diffusion bonded.Additional information concerning diffusion bonding is provided by U.S.patent application Ser. Nos. 11/897,998 and 12/238,404, which areincorporated herein by reference. In an embodiment, the stack includesmultiple sets of lamina with each set including an inlet lamina 305juxtaposed with an outlet lamina 310. Each set of juxtaposed inletlamina and outlet lamina forms a single heat exchange unit. The stack oflamina may therefore include a plurality of heat exchange units whereineach unit is formed of an inlet lamina 305 coupled to an outlet lamina310. The flow pathways for each lamina may be formed by etching on thesurface of the lamina, such as by etching on one side only of eachlamina. When the laminae are juxtaposed, the etched side of a laminaseals against the unetched sided of an adjacent, neighboring lamina.This may provide desirable conditions for heat exchange and separationof the incoming fluid (which is not pasteurized) and the outgoing fluid(which is pasteurized).

FIG. 9 shows a perspective view of an exemplary stack 805 of laminae.The stack 805 is shown in partial cross-section at various levels of thestack including at an upper-most outlet lamina 310, a mid-level inletlamina 305 a, and a lower level inlet lamina 305 b. As mentioned, thestack 805 is formed of alternating inlet lamina and outlet laminainterleaved with one another. The heaters 292 are positioned withincut-outs that extend through the entire stack 805 across all the laminaein the stack 805. The residence chamber 360 and the aligned inletopenings 320 and outlet openings 325 also extend entirely through thestack 805. The laminae may also include one or more holes 810 that alignwhen the lamina are stacked to form shafts through which alignment postsmay be inserted.

The quantity of laminae in the stack may be varied to accommodatedesired specifications for the microfluidic heat exchange system 110,such as the heating specifications. The heating specifications may bedependent on flow rate of fluid, heater power input, initial temperatureof incoming fluid, etc. In an embodiment, the stack 805 is less thanabout 100 mm long, less than about 50 mm wide at its widest dimension,and less than about 50 mm deep, with a volume of less than about 250cubic centimeters, although the dimensions may vary. In anotherembodiment, the stack 805 is about 82 mm long, about 32 mm wide at itswidest dimension, and about 26 mm deep, with a volume of about 69-70cubic centimeters, and a weight of about five pounds when dry, althoughthe dimensions may vary.

The lamina 305 and 310 may be any material capable of being patternedwith features useful for a particular application, such asmicrochannels. The thickness of the lamina may vary. For example, thelamina may have a thickness in the range of about 200 μm to about 100μm. In another embodiment, the lamina may have a thickness in the rangeof about 500 μm to about 100 μm. Some suitable lamina materials include,without limitation, polymers and metals. The lamina may be manufacturedof any diffusion bondable metal, including stainless steel, copper,titanium alloy, as well as diffusion bondable plastics. Because of theoperating pressures and temperatures involved, the need to avoidleaching of the lamina material into the heated fluid, such as water,and the desirability of multiple uses of this device before disposal, ithas been found that manufacturing the heat exchange system fromstainless steel, such as 316L stainless steel, has proven adequate,although other materials may be used as long as they withstand theoperating conditions without degradation.

The laminae are stacked in a manner that achieves proper alignment ofthe lamina. For example, when properly stacked, the inlet openings 320of all the lamina align to collectively form an inlet passage for fluidto flow into the system and the outlet openings 325 align tocollectively form an outlet passage, as shown in FIG. 9. Theproperly-aligned stack of lamina may also include one or more seats forcoupling the heaters 292 in the stack. One or more features can be usedto assist in proper alignment of the lamina in the stack, such asalignment posts and/or visual indicators of proper alignment. The stackmay include a top cover positioned on the top-most lamina and a bottomcover positioned on the bottom-most lamina. The stack may also includean external insulation wrap to prevent heat loss to the outsideenvironment.

FIG. 10 shows a perspective view of an example of an assembledmicrofluidic heat exchange system 110. The stack 805 of inlet/outletlaminae includes chemically etched upper and lower covers that seal thestack 805 against the atmosphere. These covers typically are thickerthan the laminae, and may be about 1 mm or more in thickness in anembodiment to withstand damage and the operating pressures necessary tomaintain the fluid in a single state. The cartridge heaters 292 aremounted in cavities that extend through the entire stack 805. A plate910 is secured (such as via bolts) to the stack and provides a means ofsecuring an inlet port 915 and an outlet port 920 to the stack 805. Theinlet port 915 and outlet port 920 can be piping having internal lumensthat communicate with the inlet openings 320 and outlet openings 325.

Before assembly of the stack, each hole of each lamina that is to accepta cartridge heater is designed slightly smaller than the diameter of thecartridge heater itself. After assembly of the entire stack, the hole isenlarged for a clearance fit between the hole inner diameter and thecartridge heater outer diameter, taking into account thermal expansionof the heater during operation, to provide a uniform surface for optimumheat transfer from the heater to the pasteurizer. This method avoids anypotential issues with misalignment of the shims if the holes in eachshim were to be properly sized to the cartridge heater prior toassembly.

A second plate 925 is also secured to the stack 805. The plate 925 isused to couple one or more elongated and sheathed thermocouples 930 tothe stack 805. The thermocouples 930 extend through the stack 805 andcommunicate with the laminae in the stack 805 in the region of the dwellchamber for monitoring fluid temperature in the dwell chamber. Thethermocouples that are to be inserted into solid sections of the stackutilize a slip fit for installation. The thermocouples that enter intothe fluid flow paths require a seal to prevent fluid leakage. In thesecases, the holes for accepting the thermocouples are generated after thestack is assembled by electrical discharge machining (EDM), because thistechnique generates very small debris that can easily be flushed out ofthe system, as compared with traditional drilling, which could result inlarger debris blocking some of the flow paths. Any of a variety ofsealing members, such as o-rings or gaskets, may be coupled to the stackto provide a sealed relationship with components attached to the stack,such as the plates 910 and 925, thermocouples 930, and inlet port 915and outlet port 920. It should be appreciated that the assembledmicrofluidic heat exchange system 110 shown in FIG. 10 is an example andthat other configurations are possible.

In an exemplary manufacture process, a stack of lamina is positioned ina fixture or casing and is then placed into a bonding machine, such as ahigh temperature vacuum-press oven or an inert gas furnace. The machinecreates a high temperature, high pressure environment that causes thelamina to physically bond to one another.

In an embodiment, the weight of the overall stack can be reduced byremoving some of the excess material from the sides of the stack,thereby eliminating the rectangular footprint in favor of a morematerial-efficient polygonal footprint.

FIG. 11 shows a schematic, plan view of another exemplary embodiment ofthe microfluidic heat exchange system 110. FIG. 11 is schematic and itshould be appreciated that variations in the actual configuration of theflow pathway, such as size and shape of the flow pathway, are possible.The embodiment of FIG. 11 includes a first flow pathway 1110 and asecond flow pathway 1105 separated by a transfer layer 1115. Fluidenters the first flow pathway at an inlet 1120 and exits at an outlet1125. Fluid enters the second flow pathway at an inlet 1130 and exits atan outlet 1135. The first and second flow pathways are arranged in acounterflow configuration such that fluid flows through the first flowpathway 1110 in a first direction and fluid flows through the secondflow pathway 1105 in a direction opposite the first direction. In thisregard, the inlet 1120 of the first flow pathway 1110 is located on thesame side of the device as the outlet 1135 of the second flow pathway1105. Likewise, the outlet 1125 of the first flow pathway 1110 islocated on the same side of the device as the inlet 1130 of the secondflow pathway 1105. The flow pathways may be least partially formed ofone or more microchannels or flow fields.

With reference still to FIG. 11, fluid enters the first flow pathway1110 at the inlet 1120 and passes through a heater region 1140. A heateris positioned in thermal communication with the heater region 1140 so asto input heat into the fluid passing through the heater region 1140.Prior to passing through the heater region 1140, the fluid passesthrough a heat exchange region 1145 that is in thermal communication(via the transfer layer 1115) with fluid flowing through the second flowpathway 1105. In an embodiment, the fluid flowing through the secondflow pathway 1105 is fluid that previously exited the first flow pathway1110 (via the outlet 1125) and was routed into the inlet 1130 of thesecond flow pathway 1105. As the previously-heated fluid flows throughthe second flow pathway 1105, thermal energy from the previously-heatedfluid in the second flow pathway 1105 transfers to the fluid flowingthrough the first flow pathway 1110. In this manner, the fluid in thesecond flow pathway 1105 pre-heats the fluid in the heat exchange region1145 of the first flow pathway 1110 prior to the fluid reaching theheater region 1140.

In the heater region 1140, the heater provides sufficient thermal energyto heat the fluid to a desired temperature, which may be thepasteurization temperature of the fluid. From the heater region 1140,the fluid flows into a residence chamber 1150 where the fluid remainsheated at or above the desired temperature for the residence time. Thefluid desirably remains flowing, rather than stagnant, while in theresidence chamber 1150. From the residence chamber 1150, the fluid exitsthe first flow pathway 1110 through the outlet 1125 and is routed intothe inlet 1130 of the second flow pathway 1105.

The fluid then flows through the second flow pathway 1105 toward theoutlet 1135. As mentioned, the second flow pathway 1105 is in thermalcommunication with the first flow pathway 1110 at least at the heatexchange region 1145. In this manner, the previously-heated fluidflowing through the second flow pathway 1105 thermally communicates withthe fluid flowing through the first flow pathway 1110. As thepreviously-heated fluid flows through the second flow pathway 1105,thermal energy from the heated fluid transfers to the fluid flowingthrough the adjacent heat exchange region 1145 of the first flow pathway1110. The exchange of thermal energy results in cooling of the fluidfrom its residence chamber temperature as it flows through the secondflow pathway 1105. In an embodiment, the fluid in the second flowpathway 1105 is cooled to a temperature that is no lower than the lowestpossible temperature that precludes bacterial infestation of the fluid.

In another embodiment of the device of FIG. 11, the fluid flowing intothe second flow pathway 1105 is not fluid re-routed from the first flowpathway 1110 but is rather a separate fluid flow from the same sourceas, or from a different source than, the source for the first fluid flowpathway 1110. The fluid in the second flow pathway 1105 may or may notbe the same type of fluid in the first flow pathway 1110. For example,water may flow through both pathways; or water may flow through one flowpathway and a non-water fluid may flow through the other flow pathway.In this embodiment where a separate fluid flows through the secondpathway relative to the first pathway, the separate fluid has desirablybeen pre-heated in order to be able to transfer heat to the fluid in thefirst flow pathway 1110 at the heat exchange region 1145.

As in the previous embodiments, the embodiment of FIG. 11 may be made upof multiple laminar units stacked atop one another to form layers oflaminae. In addition, the embodiment of FIG. 11 may have the same orsimilar specifications as the other embodiments described herein,including materials, dimensions, residence times, and temperaturelevels.

In another embodiment shown in FIG. 12, a microfluidic heat exchangesystem 110 purifies a single fluid. FIG. 12 represents an exemplary flowpathway configuration for a single lamina. A plurality of such laminaemay be interleaved to form a stack of lamina as described above forother embodiments. The purification of the fluid may comprisepasteurizing the fluid although pasteurization is not necessary such aswhere the device is not used for dialysis. The heat exchange systemreceives a stream of incoming fluid 1205, which splits before enteringthe heat exchange system. A first portion of the stream of incomingfluid 1205 a enters at a first inlet 1210A on one end of the system anda second portion of the stream of incoming fluid 1205 enters at a secondinlet 1210 b on the other, opposite end of the system. The two streamsof incoming fluid 1205 are distributed across the stacked laminae inalternating fashion such that there is no direct contact between the twofluid streams.

Each stream of incoming fluid 1205 enters a flow pathway 1207 and flowsalong the flow pathway toward an outlet 1215 a. One stream of fluidenters via the inlet 1210 a and exits at an outlet 1215 a positioned onthe same end of the system as the inlet 1210 b, while the other streamof fluid enters via the inlet 1210 b and exits at an outlet 1215 b onthe same end of the system as the inlet 1210 a. Each flow pathway 1207includes a first heat exchange region 1220 where heat is exchangedthrough a transfer layer between the incoming fluid and thepreviously-heated outgoing fluid flowing through a lamina immediatelyabove (or below) the instant lamina in the stack. As the fluid flowsthrough the heat exchange region 1220 it receives heat via the heattransfer and is pre-heated prior to entering a heater region 1225.

For each flow pathway 1207, the fluid then flows into the heater region1225, which thermally communicates with at least one heater, andpreferably multiple heaters, for communicating heat into the flowingfluid. The fluid is heated under pressure to a temperature at or abovethe desired threshold pasteurization temperature as described above forother embodiments. The heater region 1225 also serves as a residencechamber. The fluid flows through the residence chamber while held at orabove the desired temperature for the desired residence time. Thedesired residence time may be achieved, for example, by varying the flowrate and/or by employing a serpentine flow path of the required lengthwithin the heater region 1225. After leaving the heater region 1225, theoutgoing fluid enters a second heat exchange region 1230 where theoutgoing fluid exchanges heat with the incoming fluid flowing through alamina immediately above (or below) the instant lamina in the stack. Theoutgoing fluid then exits the flow pathways through the outlets 1215Aand 1215 b. The two streams of outgoing fluid then recombine into asingle stream of outgoing fluid 1235 before continuing on to theultrafilter to remove all or substantially all of the dead bacteriakilled by the pasteurization process.

FIG. 13A shows another embodiment of an inlet lamina that forms a spiralinlet pathway where fluid flows in an inward direction through the heatexchange system. FIG. 13B shows a corresponding outlet lamina that formsa similar spiral pathway where fluid flow in an outward direction. Aplurality of such inlet and outlet laminae may be interleaved to form astack of lamina as described above for other embodiments. The laminaeare shown having a circular outer contour although the outer shape mayvary as with the other embodiments.

With reference to FIG. 13A, the inlet lamina has a header forming aninlet 1305 where incoming fluid enters the inlet pathway. The inletpathway spirals inward toward a center of the pathway, where a heatingchamber 1310 is located. The heating chamber 1310 also serves as aresidence chamber for the fluid, as described below. One or more heatersare positioned in thermal communication with the heating chamber 1310 toprovide heat to fluid flowing in the heating chamber 1310. The heatingchamber 1310 extends across multiple laminae in the stack and includes aconduit that communicates with the outlet lamina shown in FIG. 13B. Thefluid enters the outlet lamina from the heating chamber 1310. The outletlamina has an outflow pathway that spirals outward from the heatingchamber 1310 toward an outlet 1320.

In use, the fluid enters the inlet pathway of the inlet lamina throughthe inlet 1305 shown in FIG. 13B. The fluid then flows along the spiralinlet pathway toward the heater chamber 1310. As in the previousembodiments, the incoming fluid is at a temperature that is less thanpreviously-heated fluid flowing through the outlet lamina, which ispositioned immediately above or below the inlet lamina. As the fluidflows through the inlet pathway, the fluid receives heat frompreviously-heated fluid flowing through the outlet pathway of the outletlamina. This serves to pre-heat the fluid prior to the fluid flowinginto the heating chamber 1310. The fluid then flows into the heatingchamber 1310 where the fluid receives heat from the one or more heaters.

While in the heating chamber 1310, the fluid is heated under pressure toa temperature at or above the desired threshold pasteurizationtemperature as described above for other embodiments. As mentioned, theheating chamber 1310 also serves as a residence chamber. The fluid flowsthrough the residence chamber while held at or above the desiredtemperature for the desired residence time. As in other embodiments, thedesired residence time may be achieved, for example, by varying the flowrate and/or by employing a serpentine flow path of the required lengthwithin the heater chamber 1310. After leaving the heater chamber, theoutgoing fluid enters the outlet pathway of an outlet lamina such asshown in FIG. 13B. The outgoing fluid flows outward from the heatingchamber 1310 along the spiral flow pathway toward the outlet 1320. Thespiral pathway of the inlet lamina thermally communicates with thespiral pathway of the outlet lamina across a transfer layer As theoutgoing fluid flows along the spiral pathway, it exchanges heat withthe incoming fluid flowing through an inlet lamina immediately above (orbelow) the instant lamina in the stack. The outgoing fluid then exitsthe stack of lamina via the outlet 1320 before continuing on to theultrafilter to remove all or substantially all of the dead bacteriakilled by the pasteurization process.

3. Microfluidic Heat Exchange System: Control System

The microfluidic heat exchange system 110 may include or may be coupledto a control system adapted to regulate and/or control one or moreaspects of the fluid flow through the system, such as fluid flow rate,temperature and/or pressure of the fluid, chemical concentration of thefluid, etc. FIG. 14 shows a schematic view of an exemplary heatercontrol system 1005 communicatively coupled to the microfluidic heatexchange system 110. The heater control system 1005 includes at leastone power supply 1015 communicatively coupled to a heater control unit1020, which communicates with a control logic unit 1025. The heatercontrol unit 1020 is adapted to control the power supply to the heaters,either on an individual basis or collectively to a group of heaters.This permits temporal and spatial control of heat supplied to themicrofluidic heat exchange system 110.

The heater control system 1005 may include one or more temperaturesensors 1010 positioned in or around the microfluidic heat exchangesystem 110 for sensing fluid temperature at one or more locations withinthe fluid flow path. The type of sensor can vary. In an embodiment, oneor more thermocouples are used as the sensors 1010. The sensors 1010communicate with the heater control unit 1020 and the control logic unit1025 to provide a temperature feedback loop. The heater control system1005 provides for feedback control of fluid temperature in the system toensure, for example, that fluid is being heated to the requiredpasteurization temperature and/or that the fluid is not overheated orunderheated. For example, the heater control unit 1020 in conjunctionwith the control logic unit 1025 may adjust power to one or more of theheaters based on a sensed temperature in order to achieve a desiredtemperature profile in one or more locations of the fluid flow path. Theheater control system 1005 may include other types of sensors such as,for example, pressure sensors, flow rate sensors, etc. to monitor andadjust other parameters of the fluid as desired.

The heater control system 1005 may also be configured to provide one ormore alarms, such as a visual and/or audio indication and/or atelecommunications signal, to the user or a remote monitor of systemfunctions to inform such parties when the temperature is at an undesiredlevel. For example, the control unit 1020 may comprise one or moretemperature set limits within which to maintain, for example, theresidence chamber temperature. If a limit is exceeded—i.e., if thetemperature falls below the lower operating limit or above the upperoperating limit, the control system may bypass the heater, set off analarm and cease operation of the overall water purification system untilthe problem can be diagnosed and fixed by the operator. In this regard,the control system 1005 may include a reporting unit 1030 that includesa database. The reporting unit 1030 is configured to log and store datafrom the sensors and to communicate such data to a user or monitor ofthe system at a remote site.

4. Fluid Purification System: Startup and Shutdown

Where the fluid purification system is used for dialysis, it isimportant to avoid bacterial contamination of the fluid flow path, bothwithin the heat exchanger system 110 and throughout the componentsdownstream of the heat exchanger system 110. In this regard, the heatexchanger system 110, which serves as a pasteurizer, is desirablyoperated in a manner that ensures clean fluid flow upon startup of thefluid purification system and also avoids bacterial contamination of thedownstream components, or at least mitigates the contamination effects,upon shut down (i.e., when the heaters 292 are de-powered).

In an embodiment, clean fluid flow upon startup is achieved by initiallyflowing a sterilizing liquid through the heat exchanger system 110 whilethe heaters 292 are being powered up. The sterilizing liquid then flowsthrough all the components downstream of the heat exchanger system 110until the heat exchanger system 110 attains a desired operatingtemperature. Upon the heat exchanger system 110 reaching the desiredoperating temperature, fluid flow to the heat exchanger system 110switches to water from the reverse osmosis system 125. The water passesthrough the heat exchanger system 110 (which has achieved the desiredoperating temperature) to flush the sterilizing liquid out of the flowpathway of the heat exchanger system 110. Various sterilizing solutionsmay be used. The solution, for example, can be a 1% chlorine in watermixture, or some other widely recognized water additive that can killbacteria.

The fluid purification system may be shut down as follows. The heaters292 are de-powered while fluid flow through the heat exchanger system110 is maintained. Alternatively, a sterilizing liquid may be flowedthrough the heat exchanger system 110 until the heat exchanger system110 attains near room temperature conditions. In this manner, the flowpathway is maintained in a sterilized condition as the heat exchangersystem 110 shuts down. The flow pathway of the heat exchanger system 110is then closed or “locked down” with sterilizing liquid present in theflow pathway of the heat exchanger system 110. The presence of thesterilizing liquid greatly reduces the likelihood of bacterialcontamination during shutdown.

In another embodiment, one or more valves are positioned in the flowpathway of fluid purification system wherein the valves allow acirculating flow of solution to loop through the pump 150, heatexchanger system 110, and downstream components in a recirculation loopuntil desired pasteurization conditions are achieved during startup. Thevalves are then set to allow the sterilizing liquid to be flushed fromthe system. An auxiliary component, such as a microchannel fluid heater(without heat exchange capability), can also be incorporated to providethe ability to circulated a warmed (e.g., less than 100 degrees Celsius)sterilizing liquid through the downstream components and/or through theunpowered heat exchanger system 110. The sterilizing liquid can be usedduring either a start-up or shut-down process for keeping the flowpathway and components clean over the span of weeks and/or months. Theuse of a recirculation loop for sterilizing liquid at start up isanother manner to prevent bacteria from entering the fluid purificationsystem before the heat exchanger system 110 achieves operatingtemperatures. A timing control logic may be used with a temperaturesensing capability to implement a process that ensures quality controlover the start-up and shut down processes. The control logic may beconfigured to initiate flow only after the heat exchanger system 110 ora heater attains a preset temperature.

The flow path may include one or more bypass circulation routes thatpermit circulation of cleaning and/or sterilization fluid through theflow path. The circulation route may be an open flow loop wherein fluidflowing through the circulation route is dischargeable from the systemafter use. In another embodiment, the circulation route may be a closedflow loop wherein fluid flowing the circulation route not dischargeablefrom the system. Alternately, the system may include both open andclosed circulation routes.

5. Dialysate Preparation System

The water is in a pasteurized state as it exits the water purificationsystem 5 and flows into the dialysate preparation system 10. Thedialysate preparation system 10 is configured to mix the pasteurizedwater with a supply of concentrate solutions in order to make dialysate.FIG. 15 shows a high level, schematic view of the dialysate preparationsystem 5. The embodiment of FIG. 15 is exemplary and it should beappreciated that variations are within the scope of this disclosure.

The dialysate preparation system 10 includes an acid pump 170 thatfluidly communicates with a supply of concentrated acidified dialysateconcentrate for mixing with the purified water. The water flows from thewater purification system 5 to the acid pump 170, which pumps the acidconcentrate into the water. The water (mixed with acid) then flows intoa first mixing chamber 172, which is configured to mix the water withthe acid such as by causing turbulent flow. From the first mixingchamber 172, the acid-water mixture flows toward a bicarbonate pump 174.A sensor, such as a conductivity sensor CS, may be positioned downstreamof the first mixing chamber 172. The conductivity sensor CS isconfigured to detect a level of electrolytes in the mixture. Theconductivity sensor CS may be in a closed loop communication with theacid pump 170 and a control system that may regulate the speed of theacid pump to achieve a desired level of acid pumping into the water.

The bicarbonate pump 174 pumps bicarbonate concentrate into theacid-water mixture at a level sufficient to form dialysate. Theresulting mixture of fluid flows into a second mixing chamber 177 andexits the second mixing chamber 177 as dialysate. Another sensor, suchas a conductivity sensor CS, may be positioned downstream of the secondmixing chamber 172. The second conductivity sensor CS may be in a closedloop communication with the bicarbonate pump 177. The dialysate thenflows toward the flow balancer system and the dialyzer.

6. Dialyzer

FIG. 16 is a schematic, cross-sectional view of the dialyzer 15, whichdefines a blood compartment having a blood flow pathway 205 and adialysate compartment having a dialysate flow pathway 210 separated by atransfer layer comprised of a semi-permeable membrane 215. In anembodiment, the dialyzer includes one or more microfluidic pathways suchas micro flow fields and/or microchannels. Exemplary embodiments ofdialyzers that utilize micro flow fields and/or microchannels aredescribed below. Exemplary embodiments of dialyzers comprised of flowfield dialyzers are described below. However, the dialysis systemdescribed herein can be used with any of a variety of dialyzersincluding a variety of commercially-available dialyzers.

The blood (from a patient) enters the blood flow pathway 205 via a bloodinlet 216, flows through the blood flow pathway 205, and exits via ablood outlet 217. The dialysate enters the dialysate flow pathway 210via a fluid inlet 218, flows through the dialysate flow pathway 210, andexits via a fluid outlet 219. The semi-permeable membrane 215 isconfigured to allow the transfer of one or more substances from theblood in the blood flow pathway 205 to the dialysate in the dialysateflow pathway 210, or visa-versa.

Some examples of materials that may be used as the semipermeablemembrane 215 include polymers, copolymers, metals, ceramics, composites,and/or liquid membranes. One example of a composite membrane ispolysulfone-nanocrystalline cellulose composite membrane such as AN69flat sheet membranes available from Gambro Medical. Gas-liquid contactormembranes may also be employed for transferring a substance between aliquid and gas such as for oxygenation of blood, whereby the membraneallows transfer of carbon dioxide and oxygen, such that oxygen transfersto blood from oxygen or oxygen-enriched air, and carbon dioxidetransfers from the blood to the gas. Fluid membranes may also beemployed. Fluid membranes comprise a lamina having through cutmicrochannels containing fluid and a first and second membrane supportpositioned to contain fluid in the microchannels.

When flowing through the dialyzer 15, the blood and the dialysate mayflow in a counter-flow configuration wherein blood flows through theblood flow pathway 205 in one direction and the dialysate flows throughthe dialysate flow pathway 210 in the opposite direction. The dialyzer15 is described in the context of having a counter-flow configurationalthough a cross-flow configuration may also be used. As the blood andwater flow along the membrane 215, hemodialysis occurs. The dialyzer 15is also configured to perform ultrafiltration wherein a pressuredifferential across the membrane 215 results in fluid and dissolvedsolutes passing across the membrane 215 from the blood to the dialysate.

The dialyzer 15 is also configured to perform hemodiafiltration whereinsolute movement across the semipermeable membrane 215 is governed byconvection rather than by diffusion. A positive hydrostatic pressuredifferential between the blood flow pathway 205 and the dialysate flowpathway 210 drives water and solutes across the semipermeable membrane215 from the blood flow pathway to the fluid flow pathway. Solutes ofboth small and large molecules get dragged through the semipermeablemembrane 215 along with the fluid. In a typical hemodiafiltrationprocedure, the direction of water and solute movement is oscillatedbetween moving water and solutes from the blood into the dialysate andmoving water and solutes from the dialysate into the blood. Over apredetermined span of time, there is a net zero loss and zero net gainof fluid from the blood into the dialysate. However, during discretetime periods within that span of time, there can be a net loss of fluidfrom the blood into the dialysate and a net gain of fluid into the bloodfrom the dialysate.

The dialyzer 15 may utilize microfluidic flow fields or microfluidicchannels. Exemplary embodiments of microfluidic systems for use asdialyzers are described below.

7. Flow Balancer System

The flow balancer system 20 is adapted to regulate the flow of dialysateinto and out of the dialyzer 15 to achieve various types of dialysis,including hemodialysis, ultrafiltration, and hemodiafiltration. The flowbalancer system 20 includes a first pump for pumping dialysate into adialyzer and a second pump for pumping dialysate out of the dialyzer.The system also includes a third pump that provides improved control ofa level of ultrafiltration, hemodiafiltration, or both, as described indetail below.

FIG. 17 shows a schematic view of the flow balancer system 20 includingthe dialyzer 15. The system includes an arrangement of three or morepumps that provide improved control over the type of hemodialysis beingperformed. By varying the relative pump speeds of the three pumps, anoperator can vary the level of blood filtration and can also selectivelyachieve ultrafiltration and hemodiafiltration of the blood.

The flow balancer system 20 includes plumbing that forms a plurality offluid flow pathways, which may be any type of conduit through which afluid such as dialysate may flow. The fluid flow pathways include aninlet pathway 250 through which a fluid such as unused dialysate flowsfrom the dialysate preparation system 10 toward and into the dialyzer15. At least a first pump 255 is positioned along or in communicationwith the inlet pathway 250 for pumping the fluid toward the dialyzer 15at a desired flow rate. One or more sensors S may be coupled to thefluid flow pathway for sensing one or more characteristics of theincoming fluid, such as pressure, flow rate, temperature, conductivity,etc. In addition, one or more sample ports P may be coupled to the fluidflow pathways that provide access to fluid flowing through the piping.FIG. 17 shows the sensors S and sample ports P coupled to the fluid flowpathways at specific locations, although the quantity and locations ofthe sensors S and sample ports P may vary.

The fluid flow pathways further include an outlet pathway 260 throughwhich used dialysate flows out of the dialyzer 15 toward one or moredrains 25. In some embodiments, the dialysate exiting the dialyzer maybe used to pre-heat other incoming fluids in the system, such as thewater stream entering the heat exchange and purification system, beforereaching the drain 25. The outlet pathway 260 bifurcates into two ormore outlet pathways including a main outlet pathway 260 a and asecondary outlet pathway 260 b. At least a second pump 265 is positionedalong or in communication with the main outlet pathway 260 a for pumpingthe dialysate out of and away from the dialyzer 15 through the mainoutlet pathway 260 a.

A third pump 270 is positioned along or in communication with thesecondary outlet pathway second valve 285. The third pump 270 can beused to augment fluid flow through the fluid flow pathways such as toselectively achieve differentials in flow rates between the inletpathway 250 and the outlet pathway 260 pursuant to achieving varioustypes of dialysis, including hemodialysis, ultrafiltration, andhemodiafiltration, as described more fully below. The third pump pumpsdialysate through the fluid flow pathways when the system is in dialysismode. The third pump may also pump another fluid, such as water ordisinfectant, when the system is in a different mode, such as in acalibration mode or in a cleaning mode. The third pump 270 can also beused to calibrate flow rates between the first pump 255 and the secondpump 265, as described more fully below.

In another embodiment, shown in FIG. 18, the third pump 270 ispositioned along the inlet pathway 250 upstream of the inlet 218 of thedialyzer 15. In this embodiment, the secondary outlet pathway 260branches off the inlet pathway 250 at a location downstream of the firstpump 255 and upstream of the first valve 280. The third pump 270 pumpsfluid toward the drain 25. The embodiment of FIG. 17 may be moreefficient than the embodiment of FIG. 18 because the third pump 270 inFIG. 18 pumps fresh, unused dialysate into the drain 140 while the thirdpump in FIG. 17 pumps used dialysate into the drain 25. In anotherembodiment, the third pump 270 and the second pump 265 are bothpositioned along a single, non-bifurcating outflow pathway.

Various types of pumps may be used for the first, second and thirdpumps. In an embodiment, the pumps are nutating pumps. On otherembodiments, the pumps could be rotary lobe pumps, progressing cavitypumps, rotary gear pumps, piston pumps, diaphragm pumps, screw pumps,gear pumps, hydraulic pumps, vane pumps, regenerative (peripheral)pumps, or peristaltic pumps, or any combination thereof. Other types ofpumps can also be used. The first pump 255 and the second pump 265 maybe driven by a common shaft to ensure synchrony of the pump strokes andthe volume of fluid pumped. It is understood that first pump 255 and thesecond pump 265 may also be fully independent from each other.

As mentioned, any of a variety of fluid conduits may be used to form thefluid flow pathways of the flow balancer system 20. In an embodiment, atleast a portion of the fluid flow pathway is formed of piping having aninside diameter from ⅛ inch to ½ inch. The flow rate in the piping couldrange between about 50 ml/min to about 1,000 ml/min. In an embodiment,the flow rate is in the range of between about 100 ml/min and about 300ml/min.

With reference again to FIG. 18, the fluid flow pathways further includea bypass pathway 275 that fluidly directly connects the inlet pathway250 and the outlet pathway 260. An exemplary purpose of the bypasspathway 275 is to provide a fluid flow pathway where fluid can flow intoand out of the dialysis system and bypass the dialyzer 15, such as forflushing, cleaning or calibrating the system. In an embodiment, thejunction between the inlet pathway 250 and bypass pathway 275 is locatedupstream of the fluid inlet 120 of the dialyzer 15, and the junctionbetween the bypass pathway 275 and the outlet pathway is locateddownstream of the fluid outlet 125 of the dialyzer 15. However, otherconfigurations of the bypass pathway 275 can be used to achievebypassing of the dialyzer 15.

A first valve 280 is positioned at the junction between the inletpathway 250 and the bypass pathway 275. A second valve 285 is positionedat the junction between the bypass pathway 275 and the outlet pathway260. The first valve 280 and second valve 285 are three-way valves, suchas solenoid valves, that can be used to selectively regulate fluid flowthrough the fluid flow pathways. That is, the first valve 280 can be setto either of two or more settings including (1) a dialysis settingwherein the first valve directs all incoming fluid along the inletpathway 250 toward the dialyzer 15 (as represented by arrow A in FIG.17) and prevents incoming fluid from flowing into the bypass pathway275; or (2) a bypass setting wherein the first valve 280 diverts all theincoming fluid into the bypass pathway 275 (as represented by arrow B inFIG. 17) and the prevents incoming fluid from flowing past the firstvalve toward the dialyzer 15.

The second valve 285 can also be set to either of two settings including(1) a bypass setting wherein the second valve 285 directs incoming fluidfrom the bypass pathway 275 into the outlet pathway 260 (as representedby arrow C in FIG. 17); or (2) a dialysis setting wherein the secondvalve 285 closes flow from the bypass pathway 275 such that outgoingfluid from the dialyzer outlet 125 continues to flow outward along theoutlet pathway 260 (as represented by arrow D in FIG. 17.) The firstvalve 280 and the second valve 285 are generally both set in tandem toeither the bypass setting or the dialysis setting. The system mayinclude a control and safety system that ensures that the first andsecond valves are not set to incompatible settings.

The arrangement of the various components of the dialysis system shownin FIGS. 17 and 18 are exemplary and other arrangements are possible.For example, the flow pathways and the pumps may be placed in differentlocations along the flow pathways from what is shown in FIGS. 17 and 18.In an embodiment, the third pump 270 is positioned in the flow pathwayat a location upstream of the dialyzer 15 and downstream of the firstvalve 280 or the third pump can be positioned downstream of the dialyzer15 and upstream of the second valve 285. Moreover, the system can employmore than three pumps.

8. Flow Balancer System: Operation of Pumps to Achieve Hemodialysiswithout Ultrafiltration

With reference again to FIG. 17, the flow balancer system 20 achieveshemodialysis without ultrafiltration when the flow rate through theinlet pathway 250 is equal to or substantially equal to the flow ratethrough the outlet pathway 260. In other words, hemodialysis withoutultrafiltration is achieved where the amount of dialysate flowing intodialyzer 15 via the inlet pathway 250 is substantially equal to theamount of dialysate flowing out of the dialyzer via the outlet pathway260 over a period time. This can be achieved by operating the first pump255 at a first pump rate to provide a first flow rate through the inletpathway 250 and operating the second pump 265 and the third pump 270 atrespective pump rates that collectively achieve a flow rate through theoutlet pathway 260 that is equal to the flow rate through the inletpathway 250.

In an embodiment, the system performs a hemodialysis procedure utilizingall three pumps in an active state substantially continuously throughoutthe hemodialysis procedure. The system adjusts the pump rate of thethird pump 270 to achieve a desired balance of equal flow rates betweenthe inlet pathway 250 and the outlet pathway 260. In this embodiment,the first pump 255, second pump 265, and third pump 270 are all activethroughout the hemodialysis procedure with the first and second pumpsoperating at different pump rates and the third pump operating at a pumprate that achieves a balanced flow rate between the inlet pathway 250and the outlet pathway 136. The third pump is typically operated at apump rate that is equal to the differential between the pump rate of thefirst pump and the pump rate of the second pump. In this manner, thesecond and third pumps collectively achieve a flow rate through theoutlet pathway 260 that is equal to the flow rate through the inletpathway 250.

For example, to achieve a desired flow rate of, for example, 100 ml/minthrough the dialyzer, the first pump 255 is set to provide a flow rateof 100 ml/min through the inlet pathway 250 and the second pump 265 isdeliberately set out of balance with the first pump 255, to provide, forexample, a flow rate of only 80 ml/min. This would provide a flow ratedifferential of 20 ml/min between the first pump and the second pump.The pump rate of third pump 270 is set to provide a flow rate of 20ml/min, which is equal to the differential between the flow rates of thefirst and second pumps. In this manner, the second pump 265 and thethird pump 270 collectively achieve a flow rate of 100 ml/min throughthe outlet pathway 260 which is equal to the flow rate of through theinlet pathway 250 such that the flow rates are balanced across thedialyzer. Under such conditions, waste solutes move across thedialyzer's semipermeable membrane from the blood stream into thedialysate via diffusion to perform hemodialysis.

The flow rates through the inlet pathway 250 and the outlet pathway 260may be measured using one or more of the sensors S. In an embodiment,the sensors are flow rate sensors that directly measure flow ratesthrough the inlet pathway 250 and outlet pathway 260. In anotherembodiment, the sensors are pressure sensors that provide indications asto the fluid pressure within the inlet pathway 250 and the fluidpressure within the outlet pathway 260. Fluid pressure is a function ofthe flow rate through the flow pathways and therefore provides anindirect measurement of flow rate. Where the fluid pressure in the inletpathway 250 is equal to the fluid pressure in the outlet pathway 260,this is an indication that the flow rates are balanced between the inletpathway and outlet pathway. Where the fluid pressure in the inletpathway 250 is less than the fluid pressure through the outlet pathway260, this is an indication that the flow rate through the inlet pathway250 is less than the flow rate through the outlet pathway 260. Where thefluid pressure in the inlet pathway 250 is greater than the fluidpressure through the outlet pathway 260, this is an indication that theflow rate through the inlet pathway 250 is greater than the flow ratethrough the outlet pathway 260. The system of fluid pathways may includeone or more damping mechanisms for dampening any extreme fluctuations inpressure within the fluid pathways.

In the latter two situations, the pump rate of the third pump 270 may beadjusted in response to a pressure differential between the inlet andoutlet pathways such as in a calibration procedure, to achieve abalanced flow rate between the inlet pathway 250 and outlet pathway 260.The calibration procedure may optionally be performed with the system ina calibration mode such that the first and second valves are set tocause fluid to flow through the bypass pathway 275 and bypass thedialyzer 15, as represented in FIG. 19 and described in more detailbelow. When the calibration procedure is performed by bypassing thedialyzer 15 and a pressure differential is detected between the inletand outlet pathways, the flow of the third pump 270 may be appropriatelyadjusted ‘on the fly’ to increase or decrease the third pump's speed toachieve the desired flow rate in the outlet pathway 260 without havingto turn the pump on or off. In this regard, the pressure sensors S andthe three pumps, as well as the valves 280 and 285, may be connected ina closed loop control system to achieve automatic balancing of the flowrates.

In another embodiment, a balanced flow rate between the inlet pathway250 and the outlet pathway 260 is achieved in theory at least by thefirst pump 255 and the second pump 265 operating at the same pump rateto achieve equal flow rates through the inlet pathway 250 and outletpathway 260. Although it is theoretically possible to match the flowrates of the first pump 255 and the second pump 265, various factors mayresult in the actual fluid flow rate in the inlet pathway 250 differingfrom the actual fluid flow rate in the outlet pathway 260. The factorsmay include trapped air, hardware wear, and fluid leakage, which cancause the flow rates of the first and second pumps to diverge over timefrom a preset or desired value. Typical technologies in dialysis systemsare unable to correct the flow balance for these types of factors.

Thus, there may come a time when a balanced flow rate cannot easily beachieved through use of the first and second pumps alone, and thus whenthere exists a need for correction to equalize the flow rates betweenthe inlet pathway 250 and outlet pathway 260. Where the fluid flow ratesare different, the third pump 270 can be used to correct the differingflow rates by being activated to pump fluid through the secondary outletpathway 260 b at a rate that is equal to the delta between the fluidflow rate through the inlet pathway 250 and the fluid flow rate throughthe outlet pathway 260. The system is preferably configured such thatthe first pump 255 is prevented from pumping less fluid than the secondpump 265 such that the first pump 255 always pumps at a higher rate thanthe second pump 265. The system preferably includes a control systemthat detects a condition where the first pump 255 inadvertently pumps ata slower rate than the second pump 265 and sets off an alarm or movesthe system out of dialysis mode if such a situation occurs.

According to a flow rate correction process, the sensors S (FIG. 17) areused to measure the flow rates through the inlet pathway 250 and theoutlet pathway 260. A comparison is performed between the flow ratethrough the inlet pathway 250 and the flow rate through the outletpathway 260. Where the flow rates are different, the third pump 270 isactivated from a de-activated state to cause fluid to flow into thesecondary outlet pathway second valve 285 at a rate selected to causethe overall flow rate in the outlet pathway 260 to be equal to the flowrate in the inlet pathway 250. A mechanism such as a servo mechanism maybe used to adjust the stroke volume of the first pump 255 and/or thesecond pump 265 until balance of the flow rates is restored (as may beevidenced, for example, by the presence of the same fluid pressure inboth the inlet pathway 250 and the outlet pathway 260).

As mentioned, the sensors S may be communicatively coupled to a controlsystem and to the three pumps in a closed loop system. The controlsystem includes hardware and/or software that automatically activatesand/or deactivates the third pump 270 or adjusts the pump rate of thethird pump 270 as needed in response to differences in detected flowrates from predetermined values or from each other, to equalize the flowrates between the inlet pathway 250 and outlet pathway 260. It should beappreciated that other measurements, such as fluid pressure in the inletand outlet pathways, may be used to indirectly calculate the flow ratesrather than directly measuring the flow rates. In this regard, the fluidpressures within the inlet pathway and the outlet pathway may bemeasured for any detectable change in pressure from a predeterminedvalue or from each other. The flow pathways may be adapted to beessentially non-compliant so that a small difference in the flow ratesof the first pump 255 and the second pump 265 will cause a rapidpressure change either negative or positive in magnitude.

The system may initially and/or periodically run in a calibration mode(sometimes also referred to as a UF checking mode) wherein a fluid(which may or may not be dialysate) is flowed through the flow pathwayswith the first valve 280 and second valve 285 set to the “bypasssetting” such that fluid flowing through the system bypasses thedialyzer 15 via the bypass pathway 275. FIG. 19 shows a schematicrepresentation of the system running in such a calibration mode wherethe dialyzer 15 is bypassed. In the embodiment where the system utilizesall three pumps in an active state substantially continuously throughoutthe hemodialysis procedure, the first and second pumps are initiallydeliberately set to achieve unbalanced flow rates. The sensors S in theflow pathway are then used to measure the fluid flow rate or pressurethrough the inlet pathway and the fluid flow rate or pressure throughthe outlet pathway. The third pump 270 is then set at a pump speed thatachieves a substantially balanced flow rate between the inlet pathway250 and outlet pathway 260.

In the other embodiment, the first pump 255 and second pump 265 areinitially set to achieve equal flow rates without necessarily requiringthe assistance of the third pump 270, which is initially inactive. Thesensors S in the flow pathway are then used to measure the fluid flowrate through the inlet pathway and the fluid flow rate through theoutlet pathway. Where the fluid flow rates are equal, the third pump 270remains inactive. However, where the fluid flow rates are not equal, thethird pump 270 is run at a rate that compensates for the discrepancy inflow rates between the inlet pathway 250 and outlet pathway 260. Asmentioned, the third pump 270 may operate in a closed-loop relationshipwith the flow rate sensors and/or the pressure sensors. FIG. 20 showsthe third pump 270 in phantom lines to represent the third pump may ormay not be activated depending on whether there is a flow ratedifferential between the inlet pathway 250 and outlet pathway 260. Thecalibration procedure that does not require activating and de-activatingthe third pump is preferred as the system may run more efficiently whenall three pumps are continuously operating.

After the calibration procedure is completed, the valves 280 and 285 maybe set to the “dialysis setting” such that fluid flows from the source110, through the inlet pathway 250, into the dialyzer 15, out of thedialyzer, and into the outlet pathway 260 from the dialyzer 15. Whenconfigured as such, the system can be used for dialysis by flowingdialysate into and out of the dialyzer 15 via the inlet and outletpathways, and by also by flowing blood into and out of the dialyzer.During dialysis, the previously described calibration procedure may beperiodically repeated, such as at predetermined intervals, to ensurethat the flow rates of the inlet and outlet pathways remain withindesired ranges.

In an embodiment, calibration is run only at the beginning of a dialysissession. In a more preferred embodiment, calibration is run periodicallyduring the dialysis session, to ensure that the desired flow balance ismaintained throughout the session. The control system can cycle thevalves 280 and 285 controlling incoming flow stream between the dialysissetting and the bypass setting and run the calibration steps withoutadditional interruptions to the dialysis session. During the calibrationprocess, when the dialysate fluid bypasses the dialyzer 15, dialysis ofthe blood that passes through the dialyzer during that period of time isunhampered due to no fresh dialysate being provided to the dialyzer 15,though the blood may cool slightly. As long as the calibration step canbe conducted over a relatively short period of time relative to the timebetween calibrations, the calibration has no material effect on thequality of dialysis being provided to the patient. In an embodiment, thedialysis system can be cycled between calibration for one minutefollowed by 60 minutes of dialysate being delivered through thedialyzer. In another embodiment, the dialysis system can be cycledbetween calibration for 30 seconds followed by 120 minutes of dialysatebeing delivered through the dialyzer.

FIG. 20 schematically shows the system running in a dialysis mode. Thethird pump 270 and the flow arrow 291 through the secondary outletpathway second valve 285 are shown in phantom lines to indicate that thethird pump 270 may or may not be active while the system is in dialysismode. The third pump 270 may be active in the situation where the thirdpump 270 is needed to equalize the flow rates between the inlet pathwayand outlet pathways. Or, the flow rates of the inlet and outlet pathwaysmay be equal without the assistance of the third pump 270, in which casethe third pump 270 remains inactive.

9. Flow Balancer System: Operation of Pumps to Achieve Ultrafiltration

The dialysis system achieves ultrafiltration in the situation where theflow rate through the inlet pathway 250 differs from the flow ratethrough the outlet pathway 260 such that there is an unbalanced flowrate across the dialyzer. Where the flow rate through the outlet pathway260 is greater than the flow rate through the inlet pathway 250, thedialyzer 15 pulls fluid from the blood across the semipermeable membraneby a convective process in order to compensate for the unbalanced flowrate. In an embodiment, the system utilizes all three pumpssubstantially continuously throughout the procedure and the pump rate ofthe third pump 270 is adjusted to achieve a desired flow ratedifferential between the inlet pathway 250 and the outlet pathway 260 toperform ultrafiltration. That is, the first pump 255, second pump 265,and third pump 270 are all active with the first and second pumpsoperating at different pump rates. The third pump is then operated at apump rate that intentionally achieves a desired imbalance of flow ratesbetween the inlet pathway 250 and the outlet pathway 136 sufficient tocause ultrafiltration.

For example, to achieve the removal of fluid at a rate 10 ml/min fromthe blood stream, the first pump 255 is set to provide a flow rate of100 ml/min through the inlet pathway 250 and the second pump 265 isdeliberately set out of balance with the first pump 255, to provide, forexample, a flow rate of only 80 ml/min. The third pump 270 is then setto provide a flow rate of 30 ml/min such that the second and third pumpscollectively provide a flow rate of 110 ml/min through the outletpathway 260. With a flow rate of 100 ml/min through the inlet pathway250 and a flow rate of 110 ml/min through the outlet pathway, thedialyzer 15 compensates for the 10 ml/min flow rate differential bytransferring 10 ml/min of fluid from the blood stream into thedialysate.

In another example, to achieve the addition of fluid at a flow rate of10 ml/min into the blood stream, the first pump 255 is set to provide aflow rate of 100 ml/min through the inlet pathway 250 and the secondpump 265 is again deliberately set out of balance with the first pump255, to provide, for example, a flow rate of only 80 ml/min. The thirdpump 270 is then set to provide a flow rate of only 10 ml/min such thatthe second and third pumps collectively provide a flow rate of 90 ml/minthrough the outlet pathway 260. With a flow rate of 100 ml/min throughthe inlet pathway 250 and a flow rate of 90 ml/min through the outletpathway, there is a transfer of 10 ml/min from the dialysate into theblood stream in order to compensate for the flow rate differential. Itshould be appreciated that the flow rate values in the precedingexamples and following examples are only for purpose of example and thatthe actual flow rates as well as the relative flow rates can vary toachieve a desired level of ultrafiltration or reverse ultrafiltration.

The speed of the third pump 270 can be varied to selectively vary anamount of ultrafiltration. For example, if it is determined that theultrafiltration is greater than desired when pulling fluid out of theblood, for example, the pump speed of the third pump 270 can be sloweddown, reducing the amount of extra fluid that the third pump 270 drawsout of the dialyzer. Where the ultrafiltration is not great enough whencompared against a desired predetermined value, the pump speed of thethird pump 270 may be increased in the case where fluid is being pulledout of the blood into the dialysate, for example, to draw an evengreater amount of fluid out of the dialyzer and, hence, the blood.

In another embodiment, the third pump 270 may be coupled to a source offluid such that the third pump 270 outputs extra fluid into the flowpathway via the secondary outlet pathway second valve 285, such as inthe embodiment of FIG. 18. The extra fluid introduced into the flowpathway is transferred across the semi-permeable membrane 215 into theblood.

10. Flow Balancer System: Operation of Pumps to AchieveHemodiafiltration

The dialysis system is configured to achieve hemodiafiltration byoscillating the speed of the third pump between (1) a first speed suchthat the second and third pump collectively achieve a flow rate throughthe outlet pathway that is greater than the flow rate through the inletpathway; and (2) a second speed such that the second and third pumpcollectively achieve a flow rate through the outlet pathway that is lessthan the flow rate through the inlet pathway. In this manner, the thirdpump 270 can be used to intermittently alternate the flow ratedifferential between a state where the dialyzer 15 pulls fluid from theblood stream into the dialysate and a state where the dialyzer 15 pushesfluid from the dialysate into the blood stream. Over a predeterminedspan of time, there should be a zero net loss (or substantially a zeronet loss) of fluid from the blood and a zero net gain (or substantiallya zero net gain) of fluid into the blood for the process ofhemodiafiltration. However, during that span of time, the dialyzer 15periodically transfers fluid into the blood from the dialysate andperiodically transfers fluid out of the blood into the dialysate. Ifultrafiltration is desired to be performed at the same time as thehemodiafiltration, then the pumps can be operated in such a way so thatin addition to the cycling of fluid into and out of the blood over time,there also occurs a net gain or loss of fluid to or from the blood overa predetermined span of time.

For example over an exemplary time span of ten minutes, the first pump255 is set to provide a flow rate of 100 ml/min through the inletpathway 250 and the second pump 265 is again deliberately set out ofbalance with the first pump 255, to provide, for example, a flow rate ofonly 80 ml/min. The speed of pump 270 can be cycled between a rate of 10ml/min for a period of 30 seconds and 30 ml/min for a period of 30seconds. During the periods when the speed of the third pump 270 is at arate of 10 ml/min, the total flow rate through the outlet pathway 260 is90 ml/min with the flow rate through the inlet pathway 250 at 100ml/min, resulting in an unbalanced flow rate that causes the dialyzer 15to transfer 10 ml/min of fluid into the blood stream. During the periodswhen the speed of the third pump 270 is at a rate of 30 ml/min, thetotal flow rate through the outlet pathway 260 is 110 ml/min with theflow rate through the inlet pathway 250 at 100 ml/min, resulting in anunbalanced flow rate that causes the dialyzer 15 to transfer 10 ml/minof fluid from the blood stream into dialysate. Over the span of tenminutes with alternating periods of 30 seconds as described above, thereis a net balanced flow rate of 100 ml/min across the dialyzer withoutany net addition or subtraction of fluid from the blood. This serves thepurpose of passing fluid to the blood across the membrane and then fluidfrom the blood to the dialysate across the membrane to achievehemodiafiltration of the blood and increases the removal oflarge-molecular waste products that would not otherwise be effectivelydialyzed. In this way, operation of the three or more-pump system canachieve all of hemodialysis, ultrafiltration and hemodiafiltrationthrough how the speeds of the first, second, and third pumps arecontrolled. This type of operation has heretofore not been possible inother dialysis systems.

In another embodiment, shown in FIG. 18, the third pump is located onthe inlet flow side of the dialyzer instead of on the outlet flow path,such that the first and third pumps collectively achieve the desiredinlet flow rate and the second pump achieves the desired outlet flowrate to perform one or more of hemodialysis, ultrafiltration andhemodiafiltration.

Between dialysis treatments, the flow pathways may be rinsed and/ordisinfected. A rinse fluid, such as, but not limited to disinfectantsolution and water, is routed through the flow pathways while the valvesare in the bypass setting. During rinse mode, the third pump 270 may ormay not be operated with the first pump 255 and second pump 265 toachieve fluid flow through the system.

11. Dialyzer: Exemplary Microfluidic Embodiments

As discussed above, the dialyzer may comprise a microfluidic transferdevice. Several exemplary embodiments of microfluidic transfer devicesare described below including devices with microfluidic channels or flowfields that serve as the blood flow compartment and dialysate flowcompartments of the dialyzer. In an embodiment, a flow field is amicrofluidic pathway with an aspect ratio of about 10 or more, where theaspect ratio is defined as ratio of the width of the microfluidicpathway and the depth of the microfluidic pathway and fluid flowssubstantially in the direction of the length of the microfluidicpathway.

A. Microfluidic Transfer Device Description

FIG. 21 depicts a counter current flow diagram 100 for a first fluid anda second fluid. Although the flow pathway is described in the context ofa microchannel, a flow pathway may also be used through a flow field.Moreover, although various embodiments described herein are shown withmicrochannel configurations, each embodiment could be constructed andoperate using a fluid flow field rather than a microchannel.

A first fluid enters microchannel inlet 102 and flows through upperlamina 104 to microchannel 106 by way of via 108 where the fluidcontacts transfer layer 110, which serves as the semi-permeable membrane215 of the dialyzer. Concurrently, a second fluid in microchannel 112contacts transfer layer 110 before flowing through lower lamina 114 tooutlet 116 by way of via 118. Transfer layer 110 may be a semipermeablemembrane chosen for the specific application to allow transfer of one ormore substances from the fluid in microchannel 106 to the fluid inmicrochannel 112, or visa-versa. For example, the specific applicationmay be a hemodialysis procedure.

The width of microchannels 106 and 112 will be the widest possibleconsidering operating parameters and construction requirements, such asto substantially prevent the transfer layer 110 from sagging into themicrochannels. The actual width will vary depending on certain factors,such as the rigidity of the transfer layer 110 and the pressuredifferential across the transfer layer. Typical microchannel widths arebetween 100 μm and 500 μm, and more typically between about 200 μm andabout 400 μm.

For the dialyzer, transfer layer 110 may be any material which allowsselective transfer of a target substance(s) through the transfer layer.A person of ordinary skill in the art will recognize that the membraneselection will depend on other design criteria including, withoutlimitation, the substance being transferred, other substances present inthe fluids, the desired rate of transfer, the fluids carrying thesubstance, the fluid receiving the substance, operating temperature, andoperating pressure. Suitable membranes may include, without limitation,polymer, copolymer, metal, ceramic, composites,polysulfone-nanocrystalline cellulose composite, gas-liquid contactormembranes, hollow fiber membranes, and fluid membranes. Some suitablemembranes for the transfer layer include without limitation,polysulphone, polyethersulfone, polyacrylanitrile, cellulose acetate,cellulose di-acetate, and cellulose tri-acetate.

Laminae 104 and 114 may be any material capable of being patterned withfeatures useful for a particular application, such as vias andmicrochannels or such as support structures for flow fields. Laminathickness may be between about 200 μm and about 1000 μm, with typicalthicknesses being between about 300 μm and about 500 μm. Suitable laminamaterials include, without limitation, polymers and metals. Examples ofsuitable polymeric materials include polycarbonate, polyethyleneterephthalate (PET), polyether imide (PEI), poly(methyl methacrylate)(PMMA), and halogenated polyethylene such as poly(tetrafluoroethylene)(PTFE). Metal laminae may be any that can have desired features formedtherein, such as materials that can be photo-chemically etched orotherwise machined to have desired features, including blind features.Examples include stainless steels, copper, titanium, nickel, andaluminum.

FIG. 22 shows a perspective view of one embodiment of a lamina design.Although FIG. 22 is described in the context of a microchannel, asimilar header configuration may be used for fluid flowing into a flowfield. The header side 120 of lamina 104 comprises inlet 102 forreceiving a fluid and directing the fluid to via 108 where the fluidflows through the plate to the microchannel side 122 (or flow fieldside) of the plate. The fluid then flows through the microchannels 106or flow field, where the fluid contacts the transfer layer, not shown.The inlet 102 has support structures 124 for preventing collapse ofadjacent lamina into the inlet 102. FIG. 22 discloses microchannels 106as plural parallel microchannels, however the present disclosure is notlimited to this configuration.

1. Flow Fields

As mentioned, any of the embodiments may incorporate one or more flowfields rather than microchannels. FIG. 23 shows an embodiment utilizinga flow field 126 rather than the parallel microchannels used in theembodiment of FIGS. 21 and 22. The flow field 126 may be generallyformed by a pair of opposed walls 129 that define the outer periphery ofthe flow field 126. A space is positioned between the walls and fluidflows within the space from an inlet toward an outlet. One or morediscrete support structures, such as wall segments 128, are positionedin the space between the walls. The support structures at leastpartially function to provide support to adjacent lamina to prevent thelamina from collapsing on another. The support structures also preventthe membrane from collapsing into the flow path and blocking the flow ofeither blood or dialysate. The support structures may be arranged in avariety of spatial arrangements relative to one another. The supportstructures may have a variety of shapes and sizes and may be in the formof pins, wall segments, bumps, protrusions, etc.

The support structures differ from the elongated walls or dividers thatform the microchannels in that the support structures do not definediscrete, elongated flow pathways. Rather, a plurality of the supportstructures are positioned in the general flow space between the opposedwalls 129 without specifically guiding the fluid in a particulardirection. The support structures permit more freedom of flow directionfor the fluid relative to the finely-guided directional flow of themicrochannels.

In addition, the discrete, spaced-apart nature of the support structuresresults in exposure of more transfer layer surface than where contiguousmicrochannel dividers are used. Exposure of more of the interposedtransfer layer to the fluids to be dialyzed, for example, improvesoverall device efficiency. A person of ordinary skill in the art willrecognized that it is desirable to maximize the area of the transferlayer exposed to the fluid while maintaining the integrity of thetransfer layer with sufficient support structures so that the transferlayer does not collapse into a portion of the flow field. Moreover, theflow field embodiments mitigate flow occlusion cause by entrapped airbubbles by allowing fluid to flow around the air bubbles, which may notoccur as readily in the more constricted volume of a microchannelbecause the bubble may be of a size to significantly block the flow in aparticular channel.

In the example of FIG. 23, the support structures are in the form ofwall segments 128 comprised of rectangular- or prismic-shaped bodiesthat extend upwardly from the surface of the lamina. The wall segments128 are positioned in groups such that a single group forms a columnfrom the viewpoint of FIG. 23. The entire flow field 126 includes aseries of columns. Each column has a plurality of wall segments 128aligned end-to-end and spaced from one another within the column. Eachof the columns is spaced from an adjacent column. The spacing betweenwall segments may vary within a single column, as can the spacingbetween one column and an adjacent column. Moreover, the wall segments128 can be arranged in other spatial patterns and are not limited tobeing arranged in column patterns.

FIG. 24 shows another example of a flow field 126 with the wall segments128 angled slightly relative to the long axes of the opposed walls 129.The magnitude of the angle of the wall segments relative to the opposedwalls 129 may vary. All of the wall segments 128 may be oriented at thesame angle. Alternately, the angle may vary from one wall segment 128 toanother wall segment 128 such that one or more of the wall segments 128may be oriented at one angle while other wall segments may be orientedat a different angle.

Angling the wall segments 128 can result in an alignment tolerant designwhen the device is assembled for concurrent or countercurrent flow. Itcan be desirable for one wall segment to be positioned at leastpartially atop another wall segment when the adjacent layers are stackedin order to provide proper structural support between the layers in thestack. In this regard, the wall segments 128 can have relative sizes andshapes and can also be arranged in patterns to maximize the likelihoodof the wall segments aligning atop one another when the layers arestacked. FIG. 5 shows a juxtaposition of adjacent layers in crosscurrent configuration 130 and concurrent configuration 132, each havingangled wall segments 128. The angled nature of the wall segmentsincreases the likelihood of the wall segments intersecting or stackingatop one another when the laminae are stacked. Slight movement of onelayer relative to the other in either the x or y direction will stillsupport the membrane at the intersection of the wall segments.

FIG. 26A discloses a laminate 134 having a flow field 136 wherein thesupport structures comprise plural cylindrical support posts 138.Similar to the wall segments 128 (FIG. 23), the plural support posts 138increase the surface area of the transfer layer (not shown) exposed fortransfer. Additionally, fluid is not confined to narrow channels as inmicrochannels 106 (FIG. 22), thereby allowing fluid to traverselaterally around flow occlusions such as air bubbles or contaminant.FIG. 26B shows a plan view of a pair of support structures comprised ofthe cylindrical support posts 138. FIG. 26C shows a schematic side viewof a pair of cylindrical support posts 138. The dimensions of thecylindrical support posts 138 may vary as may the relative spacingbetween adjacent cylindrical support posts 138 to provide the flow fieldwith desired flow characteristics. For example, the radius R of eachsupport post 138 may be predetermined, as may the distance S betweenadjacent support posts 138. The height H of each support post may alsovary. The support posts 138 may be prisms with circular bases, such as acylinder. However the bases of the prism may be any shape, such as arectangle, triangle, ellipse, polygon, or other geometric shape. Forinstance, FIG. 27 discloses a flow field 136 having support structuresformed of tear-drop shaped support posts 138. This embodiment isconfigured for streamlining fluid flow through the flow field 136.

In an embodiment, the size of the support posts is the minimumpossible—measured in diameter for cylindrical posts, width ofrectangular posts, or twice the average distance to the geometric centerfor irregular shapes—without puncturing the transfer layer and largeenough to allow alignment of posts of adjacent layers. The supportstructures are typically greater that zero μm and less than 1000 μm.More typically the support structures are greater than zero μm and lessthan 500 μm, such as about 100 μm to about 400 μm. A person of ordinaryskill in the art will recognize that the desired shape and size of thesupport structures will depend on various factors such as the transferlayer material and thickness, the fluids involved, manufacturingalignment tolerances, and transfer layer efficiency.

The flow field 136 may define an array of support structures 138 havinggradient densities and varying sizes as shown in FIG. 28. For instance,one end of the flow field 136 may have larger and sparse supportstructures 138, gradually decreasing in size and increasing in densityapproaching the opposite end. Additionally some or all of the flow fieldmay be treated with a surface treatment to enhance flow dynamics. Forinstance the surface may be treated to render it hydrophilic to reduceair entrapment. Alternatively, it may be treated selectively to behydrophobic in a low support-density area and hydrophilic in a highsupport-density area, encouraging entrapped air to move through thesparse area to the dense area where wicking and mechanical forces canforce the gas out. Also, the support structures 138 may be randomlydistributed throughout the flow field subject to design constraints asshown in FIG. 29.

The distance S between the support structures 138 may be the widestpossible considering operating parameters and construction requirements,such as to substantially prevent the transfer layer 110 (FIG. 21) fromsagging into the flow field 136. The actual width will vary depending oncertain factors, such as the rigidity of the transfer layer 110 (FIG.21) and the operating pressure differential across the transfer layer.Typical widths are between 100 μm and 500 μm, and more typically betweenabout 200 μm and about 400 μm.

Microchannel or flow field depth creates a transfer efficiencyadvantage. Micron scale dimensions reduce mass transfer limitations byreducing diffusion or conduction lengths through the bulk fluid, therebyincreasing the mass rate per unit area of transfer layer 110 (FIG. 21),consequently increasing efficiency and reducing device size.Microchannel or flow field depth is typically greater that zero and lessthan 1000 μm. More typically the depth is greater than zero and lessthan 400 μm. Even more typically, the depth is greater than zero andless than about 100 μm, such as from about 10 μm to 90 μm.

2. Mass Transfer Devices for use as Dialyzers

Referring to FIGS. 30 and 31, assembled mass transfer device 200, whichcan serve as a dialyzer, is comprised of laminae 202, laminae 204, andtransfer layers 206. Compression plates 208 are provided to applypressure to the layered plates 202 and 204 and transfer layers 206 toafford substantially sealed fluid microchannels or flow fields.Compression plates 208 apply pressure using, for example, fastenersconnecting the compression plates or by placing device 200 in a clampingmechanism. A person of ordinary skill in the art will recognize thatvarious additional methods of applying force to the compression platesexist in the art. Fluidic headers 210 are operably connected tomass-transfer device 200, and are fluidly connected to microchannelinlets 212 and microchannel outlets 214, for delivering fluids to theinternal microchannels 106 and 112 (FIG. 21). FIG. 31 shows twomicrofluidic transfer devices arranged in parallel, however a person ofordinary skill in the art will recognize that any number of devices maybe configured in parallel, series, or both.

The compression plates 208 may be made from any material with sufficientrigidity to evenly compress the laminae 202 and 204 and transfer layers206. Suitable materials include, without limitation, polymer, metals,ceramic, or composites. An exemplary material may be, for instance,acrylic. However, a person of ordinary skill in the art will recognizethat the compression plate material and its thickness may depend onvarious factors, for instance, the number of layers in the stack, therequired shape to affect a seal, and the operating temperatures. Thecompression plates 208 may be flat or may have a curved face, such as aconvex face, having a curvature suitable for preferably evenlydistributing pressure through the device 200.

FIG. 32 shows an assembly view of one embodiment of a microfluidictransfer device 300. Mass transfer device 300 comprises a sequencedstack of lamina held between compression plates 302. The sequenced stackcomprises head gaskets 304, and repeating subunits separated by gaskets306. The repeating subunits comprise, in order, a first lamina 308, atransfer layer 310, and a second lamina 312. The number of subunits willdepend on the application and the volumetric throughput and transfercapacity required. Additionally, devices may be connected in parallel asshown in FIG. 31. Laminae 308 and 312 are substantially similar indesign. Referring to FIG. 33, laminae 308 and 312 have fluid headers314, fluid inlet 316, support structures 318, vias 322, microchannels324 (or flow fields) located on the opposite side, and fluid outlet 326.This can be seen in more detail in the discussion of FIG. 36 below.Referring again to FIG. 32, the gaskets 304 and 306 have cutouts 325 sothat the gasket does not cover the fluid headers 314, preventingcollapse of the gasket material into the header and impeding fluid flow.The support structures 318 may transfer compression force through thestack to facilitate compression sealing throughout the stack and preventthe adjacent lamina from collapsing into the header. The supportstructures may also prevent the transfer membrane from blocking fluidflow in and through the header. Operatively connected to compressionplate 302 are fluid connectors 328, 330, 332, and 334.

FIG. 34 shows a perspective view of assembled microfluidic transferdevice 300. The compression plates 302 have apertures 336 for receivingfasteners for coupling together and compressing the stack 338. A firstfluid enters the device 300 through fluid connector 328 and exits thedevice through fluid connector 330. A second fluid enters the device 300through fluid connector 332 and exits the device through fluid connector334.

FIG. 35 provides a detailed view of the internal flow path of twosubunits of stack 400. Fluid flow paths 402 show a first fluid (e.g.,blood) entering through fluid inlet 404. Fluid inlet 404 is athrough-hole which fluidly connects the first fluid to subunits in thestack. Fluid enters the headers 405, flows around the support structures406 through the vias 408 to microchannels 410 or flow fields where itcontacts transfer layers 412. Transfer layers 412 operatively connectmicrochannels 410 or flow fields containing the first fluid andmicrochannels 414 or flow fields containing the second fluid (e.g.,dialysate) to allow transfer select substances (such as blood wasteproducts) in the fluids. For instance a mass transfer layer, e.g. amembrane, may allow for membrane permeable components of the first andsecond fluid to transfer across the membrane from one fluid to theother.

FIG. 36 is a schematic view of the fluid flow patterns of both fluidsjuxtaposed. Fluid inlet 404 provides the first fluid to inlet header422, where it flows around support structures 406 to microchannels 423,and is collected at the other end of the microchannels in outlet header424, then exits through fluid outlet 418. If the embodiment of FIG. 36included a flow field rather than microchannels 423, then the fluidwould flow from the inlet header 422, through the flow field, and towardthe outlet header 424. As the fluid flows through the flow field, itwould flow around the various support structures positioned within theflow field.

The second fluid enters through fluid inlet 416 into inlet header 426,where it is directed to microchannels 427 or flow field, and iscollected in outlet header 428 and exits through outlet 420. FIG. 36discloses a device having the first and the second fluid flowingorthogonal to each other; however a person of ordinary skill in the artwill recognize that one may configure this device for concurrent,countercurrent, or crosscurrent flow. FIG. 37 discloses thejuxtaposition of adjacent layers of another embodiment utilizing flowfields 430 and 432 rather than plural parallel microchannels.

In an embodiment, the mass transfer device is a dialyzer such that thefirst fluid is blood and the second fluid is dialysate. The blood entersthe fluid inlet 404 and flows to the inlet header 422. The blood thenflows into the flow field or microchannels toward the outlet header 424,and then exits through fluid outlet 418. The dialysate enters thedialyzer through the fluid inlet 416 and flows into the inlet header426, where it is directed to microchannels 427 or flow field, and iscollected in outlet header 428 and exits through outlet 420. As theblood and dialysate flow through their respective flow fields, solutesdiffuse across the mass transfer layer. A pressure gradient may beformed between the respective flow fields in order to achievehemodiafiltration of the blood where fluid periodically passes from thedialysate into the blood and/or from the blood into the dialysate,thereby transferring molecules by means of convective solute movementthat otherwise would be slow to cross the membrane barrier by diffusionalone. Ultrafiltration is a process in dialysis where fluid is caused tomove across a dialyzer membrane via diffusion from the blood into thedialysate for the purpose of removing excess fluid from the patient'sblood stream. Along with water, some solutes are also drawn across themembrane via convection rather than diffusion. Ultrafiltration is aresult of a pressure differential between the blood compartment and thedialysate compartment where fluid will move from a higher pressure to alower pressure.

FIG. 38 discloses an embodiment of the device 500 having alternatingmirror image subunits 502 and 504. This embodiment creates combinedfluid header 506, which directs fluid to microchannels 508 (or flowfields) through vias 510. The subunits 502 and 504 are separated by agasket 512 with a cutout for header 506. This arrangement reduces thefluid cross contamination relative to embodiments having headers withdissimilar fluids facing each other. Moreover, arranging the subunits502 and 506 in this manner allows for a single, simplified gasket designcompared to the two gasket designs shown as 304 and 306 in FIG. 32. Thisembodiment may be configured for cross flow as shown in FIG. 38 or forconcurrent or counter current flow as shown in FIG. 39.

Referring to FIG. 39, device 520 comprises subunit 522 having combinedheaders 524 and 526. Laminae 528 and 530 comprise parallel microchannels532 and 534 (or flow fields) separated by transfer layer 536. Parallelmicrochannels 532 and 534 allow concurrent flow paths 538 and 540.Alternatively, reversing the direction of either flow path 538 or 540will achieve countercurrent flow.

In yet another embodiment, the need for gaskets between subunits iseliminated entirely. FIG. 40 discloses a partial assembly view of a masstransfer device 600 where the laminae 604 have microchannels (or flowfields) and headers on both sides. This configuration allows the device600 to be assembled as alternate layers of identical transfer layers 602and laminae 604. FIG. 41 is a plan view of the front 606 and back 608 ofthe lamina 604. The lamina front 606 has a first fluid inlet 610 fluidlyconnected to first fluid inlet header 612. First fluid inlet header 612directs fluid through via 614 to first fluid microchannels 616 (or flowfield) on lamina back 608. The microchannels 616 direct fluid to via 618which fluidly connects the microchannels with first fluid outlet header620 on lamina front 606, where the first fluid exits by first fluidoutlet 622. Similarly, the lamina back 608 has second fluid inlet 624which fluidly connects to second fluid inlet header 626. Second fluidinlet header 626 is fluidly connected to via 628 which fluidly connectsthe second fluid inlet header to the second fluid microchannels 630 (orflow field) on the lamina front 606. The second fluid microchannels 630direct the fluid to via 632 which fluidly connects the second fluidmicrochannels and the second fluid outlet header 634, which is fluidlyconnected to the second fluid outlet 636.

FIG. 42 discloses the transfer layer 602 used in microfluidic transferdevice 600 (FIG. 40). The transfer layer 602 has four cutouts 638associated with the locations of the fluid headers 612, 620, 626, and634 on plate 604 (FIG. 41). While the double sided lamina 604 allows adevice with nearly half the number of lamina compared to previouslydisclosed embodiments, compression alone may not adequately seal thetransfer layer between the headers and microchannels located on the sameside of the lamina.

FIG. 43 shows a detailed view of a microfluidic transfer device 700employing double sided lamina 604. The first fluid flows from theheaders 706 through lamina 604 to microchannels 702 (or flow field).Similarly the second fluid flows from a header, not shown, on lamina 604to microchannels 704 (or flow field) located on the same side of theplate as header 706. Because the transfer layer 602 is compressedagainst adjacent layers by microchannel dividers 708 rather than a solidsurface, fluid could leak under the transfer layer allowing fluid fromheader 706 to enter microchannel 704. Transfer layer bond 710 preventsthis. Adhesives or laser welding could create the transfer layer bond710, however a person of skill in the art will recognize that one mayemploy other methods to create the bond. Such methods include but arenot limited to RF welding, ultrasonic welding, and thermal welding.

While FIG. 43 discloses a double-sided device with crosscurrent flow, itis also possible to configure a double-sided device with concurrent orcountercurrent flow. For example, FIG. 44 illustrates device 720 havingdouble-sided laminae 722 and 724 arranged to provide combined headers726 and 728. Microchannels 730 and 732 are parallel and are separated bytransfer layer 734, allowing concurrent flow paths 736 and 738. Likewisemicrochannels 740 and 742 are parallel to each other and are separatedby transfer layer 744, allowing concurrent flow paths not shown. Aperson of ordinary skill in the art will recognize that this embodimentalso allows countercurrent flow.

One embodiment of the microfluidic transfer device employs microchannelsthat are cut through the entire lamina thickness. FIG. 45 is a plan viewof a through-cut lamina 800. Lamina 800 has fluid inlet 802, fluidlyconnected to inlet header 804. Inlet header 804 is fluidly connected tovia 808. Through-cut microchannels 811 are fluidly connected to vias 808by way of microchannels 814. Microchannels 814 fluidly connectthrough-cut microchannels 811 with outlet header 816, which directsfluid flow to outlet 818. With the microchannels cut through the entirelamina thickness, the microchannel dividers may need structural support.FIG. 46 shows lamina 800 having through-cut microchannels 811 supportedby partial thickness dividers 812. To afford a robust compression seal,lamina 800 has a compression seal face 820 for compressing the transferlayer against the adjacent layer. Another embodiment of a through-cutmicrochannel lamina is shown in FIG. 47.

FIG. 47 shows a plan view of lamina 800 having microchannel dividersforming a herringbone pattern. Referring to FIG. 48, microchanneldividers 814 comprise plural partial thickness wall segments 816arranged in a herringbone pattern. Partial thickness wall segments 816alternate in the herringbone pattern such that adjacent wall segmentsare flush with opposite sides of the lamina 800. This design increasesdevice efficiency by exposing a greater surface area of the transferlayer (not shown). The partial thickness wall segments 816 mayessentially form a flow field rather than microchannels, as the partialthickness wall segments 816 do not necessarily constrain the fluid flowinto a single channel.

FIG. 49 shows an assembly view of microfluidic transfer device 900 usingthrough-cut laminae 906. Compression plates 902, operatively connectedto gaskets 904, hold and compress repeating subunits comprising, inorder, first fluid lamina 906, transfer layer 908, and second fluidlamina 910. The subunits are separated by transfer layers 912. Oneadvantage of this embodiment is the increased transfer layer exposureper microchannel. Since the through-cut microchannels are bound on twosides by transfer layers 908 and 912, which operatively connect them toadjacent plates, the transfer layer surface area per lamina is almostdoubled. This allows for fewer layers, and allows reduced costs andsmaller devices.

FIG. 50 provides a detail of the fluid flow path 1000. Fluid enters theinlet header 1002, which directs the fluid to via 1004. The fluidtravels through via 1004 to microchannel 1006, then to through-cutmicrochannel 1008. Through-cut microchannel 1008 is oriented orthogonalto through-cut microchannel 1010. Through-cut microchannels 1008 and1010 have partial thickness dividers 1012 for structural support.Additionally, dividers 1012 provide mixing without substantiallyimpeding fluid flow. Transfer layers 1014 separate and operably connectthrough-cut microchannels 1008 and 1010 to afford heat or mass transferfrom one fluid to another.

FIG. 51 discloses a detail of a through cut device 1100 having bothconcurrent and cross current flow. Device 1100 comprises plural subunits1102. Subunit 1102 comprises a transfer layer 1104 between a firstlamina 1106 and a second lamina 1108. Laminae 1106 and 1108 havethrough-cut microchannels 1110 and 1112, respectively. Microchannels1110 and 1112 are parallel to each other and orthogonal to microchannelsof adjacent subunits 1102. The subunits 1102 are separated by transferlayers 1114. Consequently, subunits 1102 have concurrent orcountercurrent flow between laminae 1106 and 1108 within subunit 1102,and crosscurrent flow between subunits.

The disclosed device may utilize fluid membranes. FIG. 52 discloses aplan view of the juxtaposition of the process fluid flow paths 1202 and1204 and the fluid membrane channels 1206. Fluid flow paths 1202 and1204 are substantially parallel to each other and substantiallyorthogonal to the fluid membrane channels 1206. Referring now to FIG.53, fluid membrane device 1300 comprises through-cut laminae separatedby fluid membranes 1304. Fluid membranes 1304 comprise through-cutlamina 1306 containing fluid and membrane supports 1311. Through-cutlamina 1308 has microchannels 1312 substantially orthogonal tomicrochannels 1314 of through-cut laminae 1302. A person of ordinaryskill in the art will recognize that the membrane supports may be anymaterial suitable for liquid membrane applications. For example andwithout limitation, a microporous polyethylene film may be used as amembrane support. A person of ordinary skill in the art will recognizethat the need for, composition and positioning of membranes support willdepend on, for example, the fluid used in the fluid membrane, theprocess fluids, and the operating temperatures and pressures.

The mass transfer device may also be configured as a fuel cell. FIG. 54discloses a fuel cell device 1400 comprising plural through-cut lamina1402 separated by a transfer layer 1404 comprising a cathode 1406, ananode 1408, and a polymer electrolyte membrane 1412 therebetween. Thedevice of FIG. 54 may contain, for instance, hydrogen in microchannels1414, and oxygen in microchannels 1416. Transfer layers 1404 areoriented such that the anode 1408 is adjacent to the microchannels 1414and the cathode is adjacent to the microchannels 1416. A person ofordinary skill in the art will recognize that this device may be usedwith any fuel cell and the transfer layer configuration will depend on,for instance, the fuels used and the operating temperature and pressure.A person of ordinary skill in the art will also recognize that thedevice may also be configured for concurrent or countercurrent flow.

FIG. 55 shows a plan view of an embodiment of a lamina of a flow fielddialyzer without header regions. In this embodiment, the flow field hasa polygonal shape with an inlet 1505 positioned at an upper point of theflow field and an outlet 1510 positioned at a lower point of the flowfield. A plurality of support structures, such as pins, is locatedwithin the flow field. For clarity of illustration, the supportstructures are not shown in the flow field of FIG. 55. The configurationof the support structures within the flow field may vary as describedabove with reference to FIGS. 23-29.

The flow field is defined by opposed walls 1517 with a spacetherebetween for fluid flow. The walls 1517 diverge from the inlet 1505such that the flow field has relatively small transverse size in theregion of the inlet 1505 and a widened transverse size in a centralregion 1520. The central region 1520 is approximately represented withan oval shape in FIG. 55, although the shape of the central region mayvary. From the central region 1520, the walls 1517 converge toward theoutlet 1510 such that the flow field has a smaller transverse size atthe outlet 1510 relative to the central region 1510. The inlet 1505supplies fluid into the flow field without any particular flow regionfor the fluid to attain a relatively even distribution before enteringthe flow field.

The relatively constrained size at the inlet 1505 relative to thecentral region 1520 results in a pressure differential between fluidflowing at the inlet relative to fluid flowing at the central region1520. That is, the pressure drops as the fluid flows into the widenedcentral region. The pressure then rises as the fluid flows toward thesmaller region of the outlet 1510. This results in an increase in fluidvelocity as the fluid flows from the inlet 1505 toward the centralregion 1520, and then a decrease in velocity as the fluid flows from thecentral region 1520 toward the outlet 1510. The flow field may vary inshape and can have any of a variety of shapes that achieve the sizedifferential between the regions of the inlet/outlet and the centralregion. For example, FIG. 56 shows a circular flow field that achievessize differentials between the regions of the inlet/outlet and thecentral region. Other shapes are possible, such as oval, diamond, etc.

In such an embodiment, no header may be required as a result of the flowfield itself acting as its own header region and attaining a relativelyeven flow distribution simply through the effect of the pressure dropbetween the relatively higher pressure, higher fluid velocity regionassociated with the incoming fluid stream immediately adjacent the inlet1505, and the relatively lower pressure, lower velocity region 1520towards the center region 1520 of the flow field, combined with thevarious supports structures such as pins that the fluid impinges uponand flows around to create an even flow distribution. As more fluidenters the flow field through the inlet 1505, the fluid already in theflow field is pushed towards and out of the outlet 1510. Moreover, thereduction in fluid velocity as the fluid flows into the central region1520 results in an increase in the residence time for fluid in the flowfield. The increased residence time may result in an increased amount ofdiffusion across the dialyzer membrane and increased efficiency of thedialyzer.

In an embodiment, the pins 1512 are arranged in a series of rows suchthat the pins essentially form channels through the flow field. Usingknown techniques, channels of a certain depth between the rows of pinscan be achieved as follows. First a master lamina may be created, forexample, by machining a suitable material, such as aluminum, to thedesired dimensions or by laser etching a sheet of suitable material,such as a polyimide sheet. In an embodiment, a sufficient amount oflaminae are used to form a rectangular flow field having dimensions ofabout 10 centimeters by about 10 centimeters although variations arepossible. An embossing master is then created from the master laminaeither by embossing a polyetherimide sheet with the previously createdmaster, or by a combination of laser etching and embossing with thepreviously created master. Finally, each lamina is created from theembossing master. It should be appreciated that variations are possiblein the method of manufacture.

In creating the master using laser etching, the paths of the laser beamscut pathways of relatively even depth into the substrate. This isrepresented schematically in FIG. 57, where the lines 1610 representsuccessive pathways of laser beams that form the channels. A channel ofrelatively even depth into the lamina is formed along the length of eachlaser pathway. However, where the laser pathways cross one another, suchas at junction 1615, the lamina is cut about twice as deep as where thelaser pathways don't cross. The increased depth at the junctions 1615 isat least partially a result of the laser energy multiplying where thetwo lasers crossing one another. This results in an undulating path foreach channel wherein each channel has a relatively uniform depth along aportion of its length and increased depth at the junctions 1615.

FIG. 58 shows an enlarged view of a portion of lamina where thelaser-formed channels intersect and have this type of undulating-floorchannel resulting from a laser-etched cut. FIG. 59 shows an enlargedview of the lamina surface showing the undulating channels and pinsformed between the channels. The embodiment shown in FIG. 59 has raisedsurfaces that are generally flat on the sides and top. In anotherembodiment, the raised surfaces are rounded on the sides and top. Theundulating channel pathway floor results in more mixing conditions inthe flow than would otherwise be achieved with a pathway floor betweenall pins of relatively equal depth, such as is typically creating whenmachining aluminum, for example. That is, the undulating channel pathwayfloor results in localized variations in flow velocity and flowdirection in each region of increased depth. This causes localizedmixing of the fluid as it flows along the regions of increased depth.The mixing tends to increase the efficiency of the device by repeatedlybringing fresh dialysate closer to the surface of the transfer membrane.

FIG. 60 shows an embodiment where alternating symmetrical laminae arestacked in a cross-current manner for separation of the inlets 1505 aand outlets 1510 a of the laminae handling the fluid to be dialyzed, forexample, from the inlets 1505 b and outlets 1510 b of the interleavedlaminae handling the dialysate. For such an embodiment, each lamina maybe substantially symmetrical about a central axis, such as square- orcircle-shaped, so that even stacking may be achieved. Almost any degreeof counter-current or cross-current or con-current flow with aheaderless flow field and appropriately located inlets and outlets maybe configured and would fall within the scope of the present invention.

To determine the feasibility of using the disclosed device forhemodialysis, one-, three-, and five-layer microchannel-based devicesand a single-layer flow-field device were fabricated. Themicrochannel-based device contained microchannels that were 100 deep and400 μm wide with 200 μm wide dividers. There are 51 channels in thearray, giving a relatively small membrane transfer area of 4.2 cm² perlayer (or transfer unit). The flow-field design had 6.3 cm² of membranetransfer area with a flow field depth of 60 μm. The laminae wereprepared and patterned using a hot emboss technique. All devices wereconfigured for cross flow and sealed using compression. The transferlayers were AN69 flat sheet membranes available from Gambro Medical.

Flow rates of fluids across the various microfluidic embodimentsdisclosed depend on the flow rate across an individual lamina and thenumber of lamina in a stack. In a microfluidic device that is being usedfor dialysis within a dialysis system, the flow rate across themicrofluidic dialyzer may be substantially matched with the flow rate ofdialysate being produced up-stream of the dialyzer. In this manner flowrates of up to 1000 ml/min may be achieved, though lower flow rates,such as 100 ml/min across either side of the membrane may be preferredfor dialysis applications outside of the clinical setting, such as homeor nocturnal dialysis.

B. Making Microfluidic Transfer Devices

Devices disclosed herein may be produced by a many of the techniquesinvolved in a fabrication approach known as microlamination.Microlamination methods are described in several patents and pendingapplications commonly assigned to Oregon State University, includingU.S. Pat. Nos. 6,793,831, 6,672,502, and U.S. Publication, Nos.2007/0029365, entitled High Volume Microlamination Production of MECSDevices, and 2008/0108122, entitled Microchemical Nanofactories, all ofwhich are incorporated herein by reference.

Microlamination consists of patterning and bonding thin layers ofmaterial, called laminae, to generate a monolithic device with embeddedfeatures. Microlamination typically involves at least three levels ofproduction technology: 1) lamina patterning, 2) laminae registration,and 3) laminae bonding. Thus, the method of the present invention formaking devices comprises providing plural laminae, registering thelaminae, and bonding the laminae. Laminae bonding is not required forall disclosed embodiments, as the registered lamina are held betweencompression plates affording a compression seal. As yet anotheralternative, certain embodiments may have at least some laminae bondedtogether in combination with compression. The method also may includedissociating components (i.e., substructures from structures) to makethe device. Component dissociation can be performed prior to, subsequentto, or simultaneously with bonding the laminae.

In one aspect of the invention, laminae are formed from a variety ofmaterials, particularly metals; alloys, including intermetallic metalsand super alloys; polymeric materials, including solely by way ofexample and without limitation, polycarbonate, polyethyleneterephthalate (PET), polyether imide (PEI), poly(methyl methacrylate)(PMMA), and halogenated polyethylene such as poly(tetrafluoroethylene)(PTFE); ceramics; and combinations of such materials. The properselection of a material for a particular application will be determinedby various factors, such as the physical properties of the metal ormetal alloy and cost. Examples of metals and alloys particularly usefulfor metal microlamination include stainless steels, copper, titanium,nickel, and aluminum. Laminae useful for the microlamination method ofthe present invention can have a variety of sizes. Generally, thelaminae have thicknesses of from about 25 μM to about 1000 μm thick,preferably from about 25 μm to about 500 μm thick, and even morepreferably from about 25 μm to 250 μm thick. Individual lamina within astack also can have different thicknesses.

1. Lamina Patterns

Lamina patterning may comprise machining or etching a pattern in thelamina. Lamina patterning may also comprise embossing, roll embossing,and/or stamping. The pattern produced depends on the device being made.Without limitation, techniques for machining or etching includelaser-beam, electron-beam, ion-beam, electrochemical, electrodischarge,chemical and mechanical material deposition or removal. The lamina canbe patterned by combinations of techniques, such as both lithographicand non-lithographic processes. Lithographic processes includemicromolding and electroplating methods, such as LIGA, and othernet-shape fabrication techniques. Some additional examples oflithographic techniques include chemical micromachining (i.e., wetetching), photochemical machining, through-mask electrochemicalmicromachining (EMM), plasma etching, as well as deposition techniques,such as chemical vaporization deposition, sputtering, evaporation, andelectroplating. Non-lithographic techniques include electrodischargemachining (EDM), mechanical micromachining and laser micromachining(i.e., laser photoablation). Photochemical and electrochemicalmicromachining likely are preferred for mass-producing devices.

One method for patterning lamina for disclosed device embodiments ismicroembossing. For instance, certain embodiments of the presentdisclosure were made using the following techniques. An Obducat NanoImprint Lithography system was used to transfer microscale patterns frommasters to polymeric parts. Master fabrication was accomplished bymicromilling masters in metal, such as aluminum. A double transferprocess using another material, such as polyether imide (PEI), as theintermediate was also used. A triple transfer process using patternedphotoresist as the starting master was also used. The pattern wastransferred from the photoresist, typically SU-8, topolydimethylsiloxane (PDMS), then to a thermoset epoxy (e.g., ConapoxyFR-1080) which then was used as the embossing master in the Obducattool, transferring the pattern to a lower melting temperature polymer,such as polyethylene terephthalate (PET). The SU-8 can be deposited andpatterned in multiple layers, allowing creation of precision multiplanemasters. These planes can be both above and below the plane with thecompression seal, allowing, for example, formation of protrudingfeatures such as sealing bosses as well as channels with multipledepths. Laminae also can be embossed on both sides simultaneously usedtwo masters. Alignment techniques such as marks and pins were usedduring prototyping. It is anticipated that volume production will beaccomplished using roll embossing and lamination techniques, also knownas conversion processes, which will include automated alignment usingvision systems.

Another method used for making disclosed embodiments was photochemicaletching of metal laminae, e.g., 316/316L stainless steel. Patternedphotoresist was used to mask both the front and back side of thelaminae, with different masking patterns for each side. Partial etchingfrom each side created intricate flow channels, including vias from oneside to the other and channels open to both sides. Small supportstructures used to stabilize the channel dividers were also created.Such structures can be used to create segmented channel dividerarchitectures, thereby increasing the active surface area of thetransfer layer.

Laser machining was also used to cut vias, inlet and outlet ports, andalignment pin holes in laminae as well as embossing masters. An ESI 5330with a 355 nm wavelength laser was used for laser machining. In volumeproduction a laser may be also used to cut vias and other penetrations.To create the vias, the angle of the laser will preferably benon-orthogonal to create a non-orthogonal via, thereby reducing deadvolumes in the flow channel. Alternatively, the vias and otherpenetrations may be created using a stamping operation. The stampingoperation may be accomplished as part of the embossing operation throughdesign of appropriate embossing/stamping masters. Non-orthogonal vias inparticular are also created by designing appropriate embossing/stampingmasters.

Laser micromachining has been accomplished with pulsed or continuouslaser action. Machining systems based on Nd:YAG and excimer lasers aretypically pulsed, while CO₂ laser systems are continuous. ElectroScientific Industries model 4420 is a typical system for Nd:YAG. Thismicromachining system uses two degrees of freedom by moving the focusedlaser flux across a part in a digitally controlled X-Y motion. Thecutting action is either thermally or chemically ablative, depending onthe material being machined and the wavelength used. The drive mechanismfor the Nd:YAG laser may be a digitally controlled servo actuator thatprovides a resolution of approximately 2 μm. The width of the throughcut, however, depends on the diameter of the focused beam.

Laminae also have been machined with CO₂ laser systems. Most of thecommercial CO₂ lasers semi-ablate or liquefy the material being cut. Ahigh-velocity gas jet often is used to help remove debris. As with theNd:YAG systems, the laser (or workpiece) is translated in the X-Ydirections to obtain a desired pattern in the material.

An Nd:YAG pulse laser has been used to cut through, for example,90-μm-thick steel shims. The line widths for these cuts wereapproximately 35 μm wide, although with steel, some tapering wasobserved. Some debris and ridging may occur along the edge of the cut onthe front side. This material may be removed easily from the surfaceduring lamina preparation, such as by surface polishing.

Laminae also may be patterned using a CO₂ laser. The CO₂ through-cutswere approximately 200 μm wide and also exhibited a slight taper. Thewidth of the CO₂ laser cut was the minimum achievable with the systemused. The part may be cleaned in a lamina preparation step using surfacepolishing to remove debris.

Pulsed Nd:YAG lasers also are capable of micromachining laminae madefrom polymeric materials, such as laminae made from polyimides. PulsedNd:YAG lasers are capable of micromachining these materials with highresolution and no recast debris. Ultraviolet wavelengths appear best forthis type of work where chemical ablation apparently is the mechanisminvolved in removing material. Clean, sharp-edged holes in the 25-50 μmdiameter range have been produced.

2. Lamina Preparation

Depending on the lamina and patterning technique used, lamina patterningmay include lamina preparation. The laminae can be prepared by a varietyof techniques. For example, surface polishing of a lamina followingpattern formation may be beneficial. Moreover, acid etching can be usedto remove any oxides from a metal or alloy lamina. Lamina preparationmay also include applying an oxide-free coating to some or all of thelaminae. An example of this would be electroplating gold onto the laminato prevent oxidation at ambient conditions.

3. Registration

Laminae registration comprises (1) stacking the laminae so that each ofthe plural laminae in a stack used to make a device is in its properlocation within the stack, and (2) placing adjacent laminae with respectto each other so that they are properly aligned as determined by thedesign of the device. It should be recognized that a variety of methodscan be used to properly align laminae, including manually and visuallyaligning laminae.

The precision to which laminae can be positioned with respect to oneanother may determine whether a final device will function. Thecomplexity may range from structures such as microchannel arrays, whichare tolerant to a certain degree of misalignment, to more sophisticateddevices requiring highly precise alignment. A person of ordinary skillin the art will recognize that microchannels on adjacent laminae thatare parallel to each other require a greater precision of alignment thatembodiments having cross current flow. Several alignment methods can beused to achieve the desired precision. Registration can be accomplished,for example, using an alignment jig that accepts the stack of laminaeand aligns each using some embedded feature, e.g., corners and edges,which work best if such features are common to all laminae. Anotherapproach incorporates alignment features, such as holes, into eachlamina at the same time other features are being machined. Alignmentjigs are then used that incorporate pins that pass through the alignmentholes. The edge alignment approach can register laminae to within 10microns, assuming the laminae edges are accurate to this precision. Withalignment pins and a highly accurate lamina machining technique,micron-level positioning is feasible.

Vision systems and thermally assisted lamina registration also can beused as desired. Additional detail concerning thermally assisted laminaregistration is provided by Patent Publication No. 2007/0029365, whichis incorporated herein by reference. A person of ordinary skill in theart also will recognize that the registration process can be automated.

4. Manufacture of Microfluidic Devices

Laminae bonding comprises bonding at least some of plural laminae one toanother to produce a monolithic device (also referred to as a laminate).Laminae bonding can be accomplished by a number of methods including,without limitation, diffusion soldering/bonding, thermal brazing,adhesive bonding, thermal adhesive bonding, curative adhesive bonding,electrostatic bonding, resistance welding, microprojection welding, andcombinations thereof. In addition to or as an alternative to bonding theregistered lamina, the disclosed device may be assembled betweencompression plates. However, for some applications, bonding the laminato the transfer layer may be preferable. Additionally, a bond or weld,such as a laser tack weld, may be used to facilitate assembly duringmanufacture.

A preferred method of device fabrication involves high through-put, lowcost fabrication techniques. Laminae patterning is accomplished usingseveral techniques, including embossing, stamping, and photochemicaletching, among others. In one preferred embodiment, assembly isaccomplished using roll techniques, such as those used in web processingor conversion industries. Polymer films are roll embossed and stamped,then laminated to form a subassembly. Metal laminae are patterned usingphotochemical etching. Abrasive waterjet techniques under developmentnow may also be used for patterning metal laminae in the future. Thesubassemblies are separated, stacked, and assembled in compressionframes. The primary sealing method is by compression from an externalframe, however, bonding techniques such as laser welding and adhesivesmay be used for portions of some embodiments. A sealant or sealingmethod may be applied to the edges to prevent external seepage throughthe membrane.

C. Heat Transfer Operations

In other embodiments, the microfluidic transfer devices disclosed hereincan be used in various heat transfer operations. As with the masstransfer devices disclosed herein, heat transfer devices can comprise astack of plural subunits to scale the device to the desired volumetriccapacity. Thermally conductive layers can be incorporated into suchdevices (e.g., positioned between the subunits) to allow heat totransfer from one fluid to another.

For example, referring to FIG. 21, in a heat transfer embodiment,transfer layer 109 can be a heat transfer layer for allowing heat totransfer from the fluid in microchannel 106 to the fluid in microchannel112, or visa-versa. In this embodiment, transfer layer 110 can be anymaterial capable of conducting heat from one fluid to another at asufficient rate for the desired application. Relevant factors include,without limitation, the thermal conductivity of the heat transfer layer09, the thickness of the heat transfer layer, and the desired rate ofheat transfer. Suitable materials include, without limitation, metal,metal alloy, ceramic, polymer, or composites thereof. Suitable metalsinclude, without limitation, iron, copper, aluminum, nickel, titanium,gold, silver, or tin. Copper may be a particularly desirable material.

Similar to the mass transfer devices described herein, the micron scaledimensions of a microfluidic heat transfer device reduces heat transferlimitations by reducing diffusion or conduction lengths through the bulkfluid, thereby increasing the heat transfer rate per unit area oftransfer layer 109 (FIG. 21), consequently increasing efficiency andreducing device size.

Disclosed embodiments also may incorporate both heat and mass transfercomponents. A person of ordinary skill in the art will recognize that anumber of configurations are possible and the desired application willdictate optimal configurations.

While this specification contains many specifics, these should not beconstrued as limitations on the scope of an invention that is claimed orof what may be claimed, but rather as descriptions of features specificto particular embodiments. Certain features that are described in thisspecification in the context of separate embodiments can also beimplemented in combination in a single embodiment. Conversely, variousfeatures that are described in the context of a single embodiment canalso be implemented in multiple embodiments separately or in anysuitable sub-combination. Moreover, although features may be describedabove as acting in certain combinations and even initially claimed assuch, one or more features from a claimed combination can in some casesbe excised from the combination, and the claimed combination may bedirected to a sub-combination or a variation of a sub-combination.Similarly, while operations are depicted in the drawings in a particularorder, this should not be understood as requiring that such operationsbe performed in the particular order shown or in sequential order, orthat all illustrated operations be performed, to achieve desirableresults.

Although embodiments of various methods and devices are described hereinin detail with reference to certain versions, it should be appreciatedthat other versions, embodiments, methods of use, and combinationsthereof are also possible. Therefore the spirit and scope of theappended claims should not be limited to the description of theembodiments contained herein.

TABLE 1 Temperature Time Pasteurization Type  63° C. (145° F.) 30minutes Vat Pasteurization  72° C. (161° F.) 15 seconds High TemperatureShort Time Pasteurization (HTST)  89° C. (191° F.) 1.0 secondHigher-Heat Shorter Time Pasteurization (HHST)  90° C. (194° F.) 0.5second Higher-Heat Shorter Time Pasteurization (HHST)  94° C. (201° F.)0.1 second Higher-Heat Shorter Time Pasteurization (HHST)  96° C. (204°F.) 0.05 second Higher-Heat Shorter Time Pasteurization (HHST) 100° C.(212° F.) 0.01 second Higher-Heat Shorter Time Pasteurization (HHST)138° C. (280° F.) 2.0 seconds Ultra High Temperature Pasteurization(UHT)

We claim:
 1. A medical system, comprising: a filtration system capableof filtering a water stream; a water purification system capable ofpurifying said water stream in a non-batch process, comprising amicrofluidic heat exchange system comprising a dwell chamber, whereinthe water stream is maintained in the dwell chamber at a pasteurizationtemperature for a period of time effective to pasteurize the waterstream; a mixing system capable of producing a stream of dialysate frommixing one or more dialysate components with the water stream in anon-batch process; and a dialyzer system, comprising a microfluidic orflow field dialyzer capable of being fluidly coupled to the stream ofdialysate and a blood stream, the dialyzer having a membrane separatingthe stream of dialysate from the blood stream, the membrane facilitatingdialysis of the blood stream; a plurality of pumps capable of pumpingthe stream of dialysate across the dialyzer; and a controlleroperatively coupled to the plurality of pumps, the controller capable ofcontrolling a flow rate of the dialysate stream through one or more ofthe plurality of pumps so as to perform one or both of the processes ofultrafiltration and hemodiafiltration on the blood stream while theblood stream is undergoing dialysis.
 2. The system of claim 1, whereinthe purification system produces an ultra high temperature pasteurizedwater stream.
 3. The system of claim 1, wherein the microfluidic heatexchange system further comprises: a fluid pathway having a water inletand a water outlet, the fluid pathway further having: (a) a first regionwhere water flows in a first direction at a first temperature; (b) aheater region downstream of the first region, the heater regionincluding at least one heater that transfers heat into water flowingthrough the heater region to increase the temperature of water flowingin the heater region to a second temperature greater than the firsttemperature; (c) a second region downstream of the heater region wherewater flows in a second direction at a temperature greater than thefirst temperature, wherein water flowing in the second region thermallycommunicates with water flowing in the first region such that heattransfers from water flowing in the second region to water flowing inthe first region resulting in a temperature reduction in the water as itflows through the second region, wherein water flows out of the pathwaythrough the outlet at a temperature less than the second temperature. 4.The system of claim 3, wherein at least a portion of the fluid pathwayis at least one microchannel.
 5. The system of claim 3, wherein thedwell chamber is downstream of the heater region and upstream of thesecond region, and wherein the water remains within the dwell chamber ator above the second temperature for at least a predetermined amount oftime relative to the fluid flow rate through the dwell chamber, prior toflowing into the second region.
 6. The system of claim 3, wherein thesecond temperature is at least 138 degrees Celsius.
 7. The system ofclaim 3, further comprising a pump upstream of the inlet and athrottling valve downstream of the outlet, wherein the pump andthrottling valve are arranged in a closed loop control arrangement formaintaining water in the fluid pathway above a saturation pressure suchthat the water does not change state at any point while present in thesystem.
 8. The system of claim 3, wherein the first region, heaterregion, dwell chamber and second region are contained within a singlelaminar body.
 9. The system of claim 1, wherein the dialyzer comprises afirst flow field comprising a first set of support structures aroundwhich the blood stream flows during operation, a second flow fieldcomprising a second set of support structures around which the dialysatestream flows during operation, and wherein the membrane comprises a masstransfer layer interleaved between the first and second flow fields,across which layer dialysis of the blood occurs when in operation. 10.The system of claim 1, wherein the plurality of pumps include: a firstpump fluidly coupled to the stream of dialysate and configured to pumpthe stream of dialysate through a fluid inlet pathway toward thedialyzer; a second pump coupled to a fluid outlet pathway from thedialyzer and configured to pump the fluid through the fluid outletpathway away from the dialyzer; and a third pump coupled to the fluidoutlet pathway.
 11. The system of claim 10, wherein the controlleroperates the first, second and third pumps to maintain balance betweenthe fluid flow rates in the inlet pathway and outlet pathway such thatsubstantially no fluid is added to or removed from the blood duringoperation.
 12. The system of claim 10, wherein the controller operatesthe first, second and third pumps to maintain balance between the fluidflow rates in the inlet pathway and outlet pathway such that a desiredamount of fluid is removed from the blood during operation.
 13. Thesystem of claim 10, wherein the controller operates the first, secondand third pumps to maintain balance between the fluid flow rates in theinlet pathway and outlet pathway such that a desired amount of fluid isadded to the blood during a time span of operation.
 14. The system ofclaim 10, wherein the controller operates the first, second and thirdpumps to achieve a desired level of hemodiafiltration by cycling thethird pump between a lower speed and a higher speed substantiallywithout a net addition of fluid to the blood.
 15. The system of claim10, wherein the controller operates the first, second and third pumps toachieve a desired level of hemodiafiltration and a desired rate of fluidaddition to the blood by cycling the third pump between a lower speedand a higher speed.
 16. The system of claim 10, wherein the controlleroperates the first, second and third pumps to achieve a desired level ofhemodiafiltration and a desired rate of fluid removal from the blood bycycling the third pump between a lower speed and a higher speed.
 17. Amedical system, comprising: a filtration system capable of filtering awater stream; a water purification system, capable of purifying thewater stream in a non-batch process comprising a microfluidic heatexchange system having a fluid pathway comprising (a) a first regioncomprising a water inlet where water flows in a first direction at afirst temperature; (b) a heater region downstream of the first region,comprising at least one heater to heat water flowing through the heaterregion to a second temperature greater than the first temperature and atleast 138° C.; (c) a dwell chamber downstream of the heater regionwherein the water remains within the dwell chamber at or above thesecond temperature for a predetermined amount of time effective toproduce a concentration of less than 10⁻⁶ colony forming units permilliliter; (d) a second region downstream of the dwell chamber wherewater flows in a second direction at a temperature greater than thefirst temperature, wherein water flowing in the second region thermallycommunicates with water flowing in the first region such that heattransfers from water flowing in the second region to water flowing inthe first region resulting in a temperature reduction in the water as itflows through the second region, so that water flowing out of thepathway through a water outlet is at a temperature less than the secondtemperature; a mixing system capable of producing a stream of dialysatefrom mixing one or more dialysate components with purified water fromthe water stream in a non-batch process; and a dialyzer system,comprising a microfluidic or flow field dialyzer fluidly coupled to thestream of dialysate and a blood stream, the dialyzer comprising amembrane separating the stream of dialysate from the blood stream, themembrane facilitating dialysis of the blood stream; at least one pumpcapable of pumping the stream of dialysate across the dialyzer; and acontroller operatively coupled to at least one pump, the controllercapable of controlling a flow rate of the dialysate stream through atleast one pump to perform water ultrafiltration, hemodiafiltration onthe blood stream while the blood stream is undergoing dialysis, or both.